Toxicology Handbook

TOXICOLOGY
HANDBOOK
TOXICOLOGY
HANDBOOK
3RD EDITION
Lindsay Murray
Mark Little
Ovidiu Pascu
Kerry Hoggett
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Elsevier Australia. ACN 001 002 357
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Practitioners and researchers must always rely on their own experience and knowledge in
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National Library of Australia Cataloguing-in-Publication entry

————————————————————————————————————————————
Murray, Lindsay, author.
Toxicology handbook / Lindsay Murray, Mark Little, Ovidiu Pascu, Kerry Hoggett.
3rd edition.
9780729542241 (paperback)
Includes index.
Toxicology–Australia–Handbooks, manuals, etc.
Toxicology–Oceania–Handbooks, manuals, etc.
Little, Mark.
Pascu, Ovidiu.
Hoggett, Kerry.
571.95
———————————————————————————————
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FOREWORD
This is the third edition of the Toxicology Handbook and confirms
clinical toxicology as a sub-specialty in Australasia.
Less than 20 years ago a small cohort of emergency doctors
independently sought overseas sub-specialty training in toxicology so
that they could bring a higher level of expertise to the management of
this heterogeneous and vulnerable group of patients in Australasian
emergency departments. They joined a small and informal collection of
clinical pharmacologists, intensivists and paediatricians to provide
telephone advice across the country through the National Poisons Centre
system.
Within a few years the collaboration flourished and they started local
training programs, implemented innovative patient-centred models of
care and coordinated research. Wider networks involving rural and
remote clinicians, psychiatry, drug and alcohol services and occupational
medicine were also formed.
It is now axiomatic that we should endeavour to deliver clinical care
that is evidence based. There is also clear evidence that patient
experience and outcomes are superior in organisations that have a clear ix
and inspirational vision, unambiguous objectives aligned to that vision
and clinicians who work in teams with a philosophy of continuous
improvement. This handbook is written by clinicians who have worked
in such a way. They have designed the content and format of this book
to allow the easy dissemination of their expertise and experience for the
benefit of patients beyond their own hospitals. It is an authentic clinical
handbook and not just a text for the shelf or study. It continues the clear
and consistent format of previous editions. The clinical approach is
based on risk assessment and enables evidence-based and pragmatic
management tailored to the individual needs of patients. This is a key
element in progressing the ideal of optimal care for the poisoned patient
irrespective of location.
The vision has always been to deliver patient care that is safe,
effective, personal, timely and efficient. I believe this handbook
represents a practical step to deliver on this vision at an individual
patient level and as part of a wider system of care.
Professor Frank FS Daly MBBS FACEM LWA

A/Chief Executive, South Metropolitan Health Service
University of Western Australia and the Centre for Clinical Research
in Emergency Medicine, Western Australian Institute for Medical
Research
PREFACE
The Toxicology Handbook was originally conceived as a distillation of
the collective experience of the clinical toxicologists of the West
Australian Toxicology Service. It was written with the aim of producing
a useful but concise bedside text to assist the clinician in treating the
acutely poisoned patient in whatever setting they might be practising
within Australasia or elsewhere. With this in mind the authors made
every effort not only to provide the necessary factual information but to
train the user to adopt a rigorous and structured risk assessment-based
approach to decision making in the context of clinical toxicology. The
second edition provided an opportunity to expand the coverage of toxins
and incorporate changes in management informed by new research.
Feedback from users of the first two editions of the handbook has
validated the practical utility of the structured risk assessment-based
approach to the management of poisoning and encouraged us to retain
this approach for the third edition. This latest edition necessarily
incorporates important information regarding poisoning from recently
marketed pharmaceuticals. It also incorporates important modifications in
x management advice, particularly in the area of envenoming, informed by
recently published clinical research.
x
Two of the original authors of the Toxicology Handbook were not

available to produce the third edition as their careers have since evolved
in other exciting directions. However, the contributions of Frank Daly
and Mike Cadogan live on in the third edition in a very real way. The
unique qualities of these two exceptional doctors provided the conceptual
framework and clinical expertise on which the Toxicology Handbook still
rests. We dedicate the third edition to Frank Daly and Mike Cadogan
together with our patients, who continue to instruct on a daily basis and
remind us just how much we have yet to learn.
Lindsay Murray Alan Gault

Mark Little David McCoubrie
Ovidiu Pascu Kirsty Skinner
Kerry Hoggett Jessamine Soderstorm
Jason Armstrong Ioana Vlad
EDITORS
Lindsay Murray MBBS FACEM, Consultant Emergency Physician,
Lismore Base Hospital, Lismore, NSW, Australia
Mark Little MBBS DTM&H (Lond) FACEM MPH&TM IDHA,
Consultant Emergency Physician and Clinical Toxicologist, Cairns
Hospital, Cairns, Qld; Associate Professor, School of Public Health
and Tropical Medicine, Queensland Tropical Health Alliance;
Consultant Clinical Toxicologist, NSW Poisons Information Centre,
Australia
Ovidiu Pascu MD FACEM, Consultant Emergency Physician and
Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA;
Clinical Toxicologist, WA Poisons Information Centre; Clinical
Senior Lecturer in Emergency Medicine, University of Western
Australia, Australia
Kerry Hoggett MBBS GCertClinTox FACEM, Consultant Emergency
Physician and Clinical Toxicologist, Royal Perth Hospital, Perth,
WA; VMO Clinical Toxicologist, NSW and WA Poisons Information
Centres; Clinical Senior Lecturer, University of Western Australia;
Adjunct Clinical Lecturer, University of Notre Dame, WA, Australia xi
CONTRIBUTORS
Jason Armstrong MBChB FACEM, Consultant Emergency Physician and
Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA;
Clinical Senior Lecturer in Emergency Medicine, University of
Western Australia; Medical Director, WA Poisons Information Centre;
Consultant Clinical Toxicologist, NSW Poisons Information Centre,
Australia
Alan Gault MBChB BAO FACEM, Consultant Emergency Physician
and Clinical Toxicologist, Sir Charles Gairdner Hospital, Perth, WA;
Lecturer, University of Western Australia, Australia
David McCoubrie MBBS FACEM, Consultant Emergency Physician and
Clinical Toxicologist, Royal Perth Hospital, Perth, WA; Consultant
Clinical Toxicologist, WA and NSW Poisons Information Centres,
Australia
Kirsty Skinner MBChB FACEM, Consultant Emergency Physician and
Clinical Toxicology Fellow, Royal Perth Hospital, Perth, WA,
Australia
Jessamine Soderstrom MBBS FACEM Grad Cert Toxicology, Consultant
xii Emergency Physician and Clinical Toxicologist, Royal Perth
Hospital, Perth, WA; Clinical Senior Lecturer, University of Western
xi
Australia, Australia
i
Ioana Vlad MD FACEM, Consultant Emergency Physician and Clinical

Toxicology Fellow, Sir Charles Gairdner Hospital, Perth, WA,
Australia
REVIEWERS
David Banfield BMed MPH MMedSc DCH FACEM, Emergency
Physician and Co-Director, Calvary Health Care ACT, Bruce, ACT;
Emergency Medicine Training Clinical Lecturer, Australian National
University Medical School, Canberra, ACT, Australia
David Caldicott BSc(Hons)-[NUI] MBBS(Lond) FCEM Dip Clin Tox,
Consultant Emergency Physician, Clinical Senior Lecturer, Australian
National University, Canberra, ACT; Coordinator of the ACT
Investigation of Novel Substances (ACTINOS) Group, Canberra,
ACT, Australia
Jon Hayman MBBS FACEM, Director of Emergency Medicine Training,
Royal Prince Alfred Hospital, Sydney, NSW; Chair of the Emergency
Medicine State Training Council Health Education and Training
Institute, NSW; Clinical Senior Lecturer, Faculty of Medicine,
University of Sydney, Sydney, NSW, Australia
Paul Jennings BN GradCertAdvNsg AdvDipMICAStud GradCertBiostats
GCHPE MClinEpi PhD, Department of Community Emergency
Health and Paramedic Practice, Monash University, Melbourne, Vic;
Ambulance Victoria, Melbourne, Vic, Australia xiii
Slade Matthews BmedSc(Hons) PhD DipEd GradCertEd(Higher Ed),
Senior Lecturer, Sub-Dean Medical Program Stage 1, School of
Medical Sciences (Pharmacology), Sydney Medical School,
University of Sydney, Sydney, NSW, Australia
CHAPTER 1
APPROACH TO THE POISONED PATIENT
1.1 Overview 2
1.2 Resuscitation 4
1.3 Risk assessment 12
1.4 Supportive care and monitoring 14
1.5 Investigations 16
1.6 Gastrointestinal decontamination 19
1.7 Enhanced elimination 26
1.8 Antidotes 32
1.9 Disposition 32
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1.1 OVERVIEW
Acute poisoning is a common emergency medicine presentation.

Between 150 and 400 acute poisoning presentations annually can be
expected for each 100 000 population served by an emergency
department. Acute poisoning is a dynamic medical illness that frequently
represents a potentially life-threatening exacerbation of a chronic
psychosocial disorder. However, this is a highly heterogeneous patient
population: deliberate self-poisoning, recreational drug abuse,
occupational poisoning and envenoming challenge with myriad potential
presentations. The clinician needs a robust and simple clinical approach
that can address this heterogeneity, but that allows the development of a
management plan tailored to the individual patient at that particular
presentation at that particular medical facility.
2
Risk assessment is pivotal to that robust approach. It is a distinct
cognitive process through which the clinician attempts to predict the
2
likely clinical course and potential complications for the individual at

TOXICOLOGY HANDBOOK
that particular presentation. Risk assessment should wherever possible be

quantitative and take into account the agent, dose and time of ingestion,
clinical features and progress, and individual patient factors (e.g. weight
and co-morbidities).
Toxicology management guidelines frequently focus on the agent
involved. This makes adaptation of treatment recommendations to an
individual patient in a particular location difficult. A risk-assessment-
based approach ensures the clinician addresses potentially time-critical
management priorities in an appropriate order, but avoids unnecessary
investigations or interventions.
Risk assessment is secondary only to resuscitation in the
management of acute poisoning. It allows subsequent management
decisions regarding supportive care and monitoring, investigations,
decontamination, use of enhanced elimination techniques, antidotes and
disposition to be made in a sensible structured manner.
Ideally, this risk-assessment-based approach is supported by a
healthcare system designed to address both the medical and the
psychological needs of the poisoned patient. Where the medical needs of
a patient exceed local resources, a risk-assessment-based management
approach ensures that this is identified early and disposition planning and
communication occur in a proactive manner within that organised system.
In this handbook, the authors offer a systematic risk-assessment-
based approach to the management of acute poisoning as it presents to
the emergency department (see Table 1.1.1). Separate chapters cover the
pharmaceutical, chemical and natural toxins of most importance to the
practitioner in emergency departments in Australia and New Zealand. It
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TABLE 1.1.1 Risk-assessment-based approach to poisoning
Resuscitation
Airway
Breathing
Circulation
Detect and correct
— Hypoglycaemia
— Seizures
— Hyper-/hypothermia
Emergency antidote administration
Risk assessment
Agent(s)
Dose(s)
Time since ingestion
Clinical features and course
Patient factors
Supportive care and monitoring
3
Investigations
Screening—12-lead ECG, paracetamol, blood glucose level (BGL)
Specific
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Decontamination
Enhanced elimination
Antidotes
Disposition
will also be of use to ambulance and emergency paramedic personnel

and staff of general intensive care units. The approach to acute poisoning
presented in this book is honed at the bedside and on the telephone. The
authors collectively have directly cared for many thousands of patients in
the Western Australian Toxicology Service and offered consultation in
thousands more acute poisonings across Australia and overseas via the
Western Australian, New South Wales, Victorian and Queensland Poisons
Information Centres (PICs). The agents covered are carefully selected to
cover all common poisonings, rare but life-threatening poisonings and
poisonings where particular interventions make a difference to outcome,
or which result in frequent consultations with clinical toxicologists
through the PIC network. Chapters are also offered on the important
antidotes and antivenoms with practical information on administration,
dose and adverse effects. All chapters have a risk assessment. All
chapters have special sections on ‘pitfalls’ and ‘handy tips’. These are
not for show! They are designed to respond to the real questions and
mistakes that regularly occur in clinical practice across Australasia.
Clinical toxicology has rightly become an area of expertise of the
emergency doctor but the infinite variation in presentation constantly
confounds and surprises all of us. We hope that the information in this
book, when combined with a structured approach, will improve the care
delivered to the poisoned patient.
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Poisoning is most frequently the presentation of an individual
suffering from exacerbation of very significant underlying psychiatric,

social or drug and alcohol problems. Excellence in care of the poisoning
delivered in a compassionate manner offers an opportunity to intervene
and produce a happy outcome in this vulnerable group of patients.
1.2 RESUSCITATION
INTRODUCTION
Poisoning is a leading cause of death in patients under the age of 40
years and is a leading differential diagnosis when cardiac arrest occurs in
a young adult.
Unlike cardiac arrest in the older population, resuscitation following
acute poisoning may be associated with good neurological outcomes
4 even after prolonged periods (hours) of cardiopulmonary resuscitation
(CPR). Therefore, while poisoning is considered part of the differential
4
diagnosis in a patient with cardiac arrest, resuscitation (see Table 1.2.1)

TOXICOLOGY HANDBOOK
should continue until expert advice can be obtained. Extracorporeal

membrane oxygenation therapy (ECMO) may provide life-saving
bridging therapy in selected cases of severe refractory shock or adult
respiratory distress syndrome.
Attempts at decontamination of the skin or gastrointestinal tract
almost never take priority over resuscitation and institution of supportive
care measures.
AIRWAY, BREATHING AND CIRCULATION

Acute poisoning is a dynamic medical illness and patients may
deteriorate within a few minutes or hours of presentation. Altered
TABLE 1.2.1 Resuscitation
Airway
Breathing
Circulation
Detect and correct:
Seizures
Always generalised when due to toxicological causes
Benzodiazepines first-line
Hypoglycaemia
Check bedside blood glucose level (BGL) in all patients with altered
mental status
Treat if BGL <4.0 mmol/L
Hyper-/hypothermia
Temp >38.5°C prompts urgent intervention
Emergency antidote administration
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conscious state, loss of airway protective reflexes and hypotension are

common threats to life in the poisoned patient.
As in all life-threatening emergencies, attention to airway, breathing
and circulation are paramount. These priorities are usually managed
along conventional lines. Basic resuscitative and supportive care
measures ensure the survival of the vast majority of patients.
Although commonly used to describe a patient’s mental status,
clinical scores such as the Glasgow Coma Scale (GCS) or Alert-Verbal-
Pain-Unresponsive (AVPU) system have never been systematically
validated across all poisonings. A patient’s ability to guard their airway
is not well correlated to GCS. An increased risk of aspiration has been
noted with GCS less than 15. Moreover, a patient’s ability to guard
the airway and ventilate effectively may change within a short period
of time.
In some specific situations, standard resuscitation algorithms do not
5
apply (see Table 1.2.2).
DETECT AND CORRECT SEIZURES
TOXICOLOGY HANDBOOK
Toxic seizures are generalised, and can usually be controlled with
intravenous benzodiazepines (e.g. diazepam, midazolam or
clonazepam). The most common causes of seizures in poisoned patients
in Australasia are venlafaxine, tramadol, amphetamines and bupropion.
Seizures related to ethanol or benzodiazepine withdrawal are also
common.
The presence of focal or partial seizures indicates a focal
neurological disorder that is either a complication of poisoning or due to
a non-toxicological cause, and prompts further investigation.
Barbiturates are second-line therapy for refractory seizures in acute
poisoning. Pyridoxine may be indicated in intractable seizures secondary
to isoniazid.
Phenytoin is contraindicated in the management of seizures related
to acute poisoning because of poor efficacy and the potential to
exacerbate sodium channel blockade, which may be a causative
mechanism.
DETECT AND CORRECT HYPOGLYCAEMIA

Hypoglycaemia is an easily detectable and correctable cause of
significant neurological injury. Bedside blood glucose level (BGL)
estimation should be performed as soon as possible in all patients with
altered mental status.
If the blood glucose is less than 4.0 mmol/L, 50 mL of 50% dextrose
should be given intravenously (5 mL/kg 10% dextrose in children) to
urgently correct hypoglycaemia. The result may be confirmed later with
a formal BGL measurement.
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6
6
TOXICOLOGY HANDBOOK APPROACH TO THE POISONED PATIENT
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not apply
Life-threat Mechanism Agent(s) Comments

AIRWAY
Airway Corrosive injury to ● Alkalis ● Stridor, dysphagia and dysphonia indicate

compromise oropharynx ● Acids airway injury and potential for imminent
● Glyphosate airway compromise
● Paraquat ● Early endotracheal intubation or surgical
airway often required
BREATHING
Acidosis Various ● Ethylene glycol ● Until late in the clinical course there is usually
Acidaemia ● Methanol prominent respiratory compensation
● Salicylates ● Intubation and ventilation at standard settings
worsens acidaemia and precipitates rapid
clinical deterioration, if not death
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● Avoid normo- or hypoventilation
● Maintain hyperventilation and consider bolus
IV sodium bicarbonate 1–2 mmol/kg to
prevent worsening of acidaemia
Hypoventilation Opioid mu receptor ● Opioids ● Prompt administration of naloxone may

stimulation obviate need for intubation and ventilation
Respiratory failure Cholinergic crisis ● Carbamates ● Rapid administration of atropine by serial

● Nerve agents doubling of atropine dose to achieve dry
● Organophosphates respiratory secretions may restore adequate
oxygenation
Hypoxaemia Oxygen free radical- ● Paraquat ● Avoid supplemental oxygen; if hypoxia

mediated cellular occurs, titrate supplemental oxygen to
injury, particularly maintain oxygen saturation of ~90% or PaO2
type II 60 mmHg
pneumocytes
CIRCULATION
Ventricular Hypocalcaemia ● Hydrofluoric acid ● Defibrillation alone unlikely to be efficacious

fibrillation ingestion or extensive ● Bolus IV calcium (e.g. 60–90 mL 10% calcium
cutaneous burns gluconate) repeated as required every 2
minutes until defibrillation restores perfusing
rhythm
Ventricular Fast Na+ channel ● Chloroquine/ ● Cardioversion or defibrillation unlikely to be

tachycardia blockade hydroxychloroquine efficacious
● Cocaine ● Urgently intubate and hyperventilate
● Flecainide ● Bolus IV sodium bicarbonate 1–2 mmol/kg
● Local anaesthetic repeated every 1–2 minutes until restoration
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agents of perfusing rhythm
● Procainamide ● Do not await determination of serum pH prior
● Propranolol to intubation and sodium bicarbonate boluses
● Quinine ● Lignocaine is third-line therapy when pH is
● Tricyclic established at >7.5
antidepressants ● Amiodarone and Vaughan Williams type la
antidysrhythmic agents (e.g. procainamide)
are contraindicated
Continued
7

8
8
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not
apply—cont’d

CIRCULATION cont’d
Ventricular ectopy/ Toxin-induced ● Chloral hydrate ● Cardioversion or defibrillation unlikely to be

ventricular myocardial ● Hydrocarbons efficacious
tachycardia sensitisation to ● Organochlorines ● Administer IV beta-blockers, titrate to ectopy
catecholamines response
Cardiovascular Fast sodium channel ● Local anaesthetic ● Consider intravenous lipid emulsion in
collapse/arrest blockade agents addition to standard resuscitation protocols
Refractory Various ● Calcium channel ● High-dose insulin therapy

cardiogenic blockers
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hypotension ● Propranolol
● Local anaesthetic
agents
Tachycardia Central and peripheral ● Amphetamines ● Beta-blockers contraindicated

sympathomimetic ● Cocaine ● Administer IV benzodiazepines, titrated to
response gentle sedation and heart rate control
Supraventricular Adenosine antagonism ● Theophylline ● Adenosine ineffective

tachycardia — Beta-blockers titrated to effect
— Urgent haemodialysis indicated
Hypertension Central and peripheral ● Amphetamines ● Beta-blockers contraindicated

sympathomimetic ● Cocaine ● Administer IV benzodiazepines, titrated to
response gentle sedation and heart rate control
● If further therapy necessary use agents that
can be given by titratable intravenous infusion
— Glyceryl trinitrate (GTN)
— Phentolamine
— Sodium nitroprusside
Asystole Na+–K+-ATPase pump ● Digoxin ● Usual resuscitation interventions futile

Bradycardia inhibition ● Digoxin-specific antibodies
Tachycardia
Bradycardia Calcium channel ● Calcium channel ● Atropine and pacing unlikely to be efficacious
Hypotension blockade blockers ● Bolus IV calcium (e.g. 60 mL 10% calcium
Cardiac conduction gluconate) may provide temporary
defects haemodynamic stability by increasing HR and
BP, while other treatments are organised
● High-dose insulin therapy
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Acute coronary Central and peripheral ● Amphetamines ● Beta-blockers contraindicated
syndrome sympathomimetic ● Cocaine ● Benzodiazepines
response ● GTN
● Antiplatelet and anticoagulation therapy if no
neurological deficits (otherwise cranial CT
first)
● Reperfusion therapy along conventional lines
Continued
9

10
10
TABLE 1.2.2 Specific resuscitation situations in toxicology where conventional algorithms or approaches may not
apply—cont’d

OTHER
Hyperkalaemia Na+–K+-ATPase ● Digoxin ● Calcium salts are contraindicated

pump inhibition ● Digoxin-specific antibodies
Hypoglycaemia Hyperinsulinaemia ● Sulfonylureas ● Difficult to maintain euglycaemia with

dextrose supplementation alone
● Octreotide administration decreases
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requirement for dextrose supplementation
Seizures Inhibition of GABA ● Isoniazid ● IV pyridoxine 1 g per gram of isoniazid

production ingested, up to 5 g
Seizures Adenosine ● Theophylline ● Urgent haemodialysis indicated

antagonism
Hypoglycaemia in acute poisoning is associated with numerous

agents including insulin, sulfonylureas, beta-blockers, quinine,
chloroquine, salicylates and valproic acid.
DETECT AND CORRECT HYPER-/HYPOTHERMIA

Hyperthermia is associated with a number of life-threatening acute
poisonings and is associated with poor outcome.
A temperature greater than 38.5°C during the resuscitation phase
of management is an indication for continuous core-temperature
monitoring.
A temperature greater than 39.5°C is an emergency that requires
prompt management to prevent multiple organ failure and neurological
injury. Neuromuscular paralysis with intubation and ventilation leads to a
cessation of muscle-generated heat production and a rapid reduction of
temperature.
11
Profound hypothermia (core temperature <29°C) may mimic or cause
cardiac arrest. Clinical manifestations include coma, fixed and dilated
pupils, bradycardia (usually atrial fibrillation) and hypotension. Vital
TOXICOLOGY HANDBOOK
signs may be difficult to elicit and the cardiac rhythm may degenerate to
ventricular fibrillation or asystole. In the patient with undetectable vital
signs, aggressive exogenous rewarming is indicated while CPR
continues. Cardiopulmonary bypass or extracorporeal membrane
oxygenation (ECMO), if available, is the most effective means. An
alternative measure is pleural lavage through an intercostal catheter with
large volumes of fluid warmed to 40–45°C.
EMERGENCY ANTIDOTE ADMINISTRATION

Administration of antidotes is sometimes indicated during the
resuscitation phase of management. As with all drugs, antidotes have
indications, adverse effects and contraindications. The decision to
administer an antidote during resuscitation will depend on the perceived
benefit compared to possible adverse effects.
Examples where early administration of an antidote is necessary to
ensure a successful resuscitation include intravenous sodium bicarbonate
in tricyclic antidepressant poisoning, naloxone in severe opioid
poisoning, atropine in severe organophosphorus agent poisoning and
digoxin-specific antibodies for patients with suspected digoxin poisoning
with cardiovascular compromise.
References
Albertson TE, Dawson AH, de Latorre F et al. TOX-ACLS: Toxicologic-oriented
advanced cardiac life support. Annals of Emergency Medicine 2001; 37:S78–S90.
Australian Resuscitation Council. Adult advanced life support: Australian Resuscitation
Council guidelines 2006: Guideline 11.6. Emergency Medicine Australasia 2006;
18:337–356.
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De Lange DW, Sikma MA, Meulenbelt J. Extracorporeal membrane oxygenation in
the treatment of poisoned patients. Clinical Toxicology 2013; 51:385–393.

Gunja N, Graudins A. Management of cardiac arrest following poisoning. Emergency
Medicine Australasia 2011; 23:16–22.
Isbister GK, Downes F, Sibbritt D et al. Aspiration pneumonitis in an overdose
population: frequency, predictors, and outcomes. Critical Care Medicine 2004;
32:88–93.
Kopec KT, Brent J, Banner W et al. Management of cardiac dysrhythmias following
hydrocarbon abuse: clinical toxicology case from NACCT acute and intensive
care symposium. Clinical Toxicology 2014; 52:141–145.
Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: Cardiac arrest in special
situations: 2010 American Heart Association guidelines for cardiopulmonary and
emergency cardiovascular care. Circulation 2010; 122:S829–861.
1.3 RISK ASSESSMENT
12 Risk assessment should occur as soon as possible in the management of

the poisoned patient. Only resuscitation is a greater priority. Risk
12
assessment is a distinct quantitative cognitive step through which the

clinician attempts to predict the likely clinical course and potential
TOXICOLOGY HANDBOOK
complications for the individual patient at that particular presentation.

The five key components of the history and examination required to
formulate a risk assessment are listed in Table 1.3.1.
Risk assessment is pivotal as it allows the clinician to identify potential
problems and make specific balanced decisions about all subsequent
management steps (supportive care and monitoring, screening and
specialised testing, decontamination, enhanced elimination, antidotes and
disposition).
Provided their mental status is normal, patients with deliberate
self-poisoning are generally both willing and able to give a good history
from which an accurate risk assessment can be constructed. Doctors
ignore the patient’s history at their peril.
If altered mental status precludes obtaining a direct history, back-up
strategies are employed to gather the necessary information. These
include:
1 Asking ambulance officers or family to search for agents
2 Counting missing tablets
TABLE 1.3.1 Information required to formulate a risk assessment
1 Agent(s)
2 Dose(s)
3 Time since ingestion
4 Clinical features and progress
5 Patient factors (weight and co-morbidities)
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3 Checking medical records for previous prescriptions

4 Questioning relatives about agents potentially available to the patient.
Under these circumstances, the risk assessment is less accurate and is

often based on a ‘worst-case scenario’. This is commonly the case with
small children where ingestions are rarely witnessed. As the clinical
course progresses, the risk assessment and management plan may be
refined.
In unknown ingestions, the patient’s clinical status is correlated with
the clinician’s knowledge of the agents commonly available in that
geographical area. For example, CNS and respiratory depression
associated with miotic pupils indicates opioid intoxication in a young
adult male in urban Australia, but is more likely to indicate
organophosphate intoxication in rural Sri Lanka.
The agent, dose and time since ingestion should correlate with the
patient’s current clinical status. If they do not, the risk assessment needs 13
to be reviewed and revised.
Acute poisoning is a dynamic process and important decisions can
TOXICOLOGY HANDBOOK
often be made at particular time points. For example, following tricyclic
antidepressant self-poisoning, life-threatening events occur within 6
hours (and usually within the first 2 hours) of ingestion. Therefore,
low-risk patients can be identified on clinical grounds at 6 hours
post-ingestion. In contrast, following deliberate self-poisoning with
sustained-release calcium channel blockers, patients may not exhibit
clinical features of poisoning during the first few hours. Indeed, the risk
assessment anticipates delayed severe cardiovascular effects.
In the majority of cases, the risk assessment allows early recognition
of medically trivial poisonings. This reassures attending staff, family
and patient and permits the avoidance of unnecessary investigations,
interventions and observation. Early psychosocial assessment and
discharge planning may begin. This usually shortens hospital length
of stay.
Less commonly, but very importantly, risk assessment allows early
identification of potentially serious poisoning and the implementation of
a tailored proactive management plan. Balanced decisions about
gastrointestinal decontamination can be made and appropriate
investigations selected. If a specialised procedure or antidote might be
required in the next few hours, early communication and disposition
planning may begin.
ROLE OF THE POISONS INFORMATION CENTRE

The clinician’s ability to construct an accurate risk assessment relies on
knowledge and experience of the toxic agents concerned. Although this
is straightforward for many exposures, new or unusual agents are
ERRNVPHGLFRVRUJ
frequently encountered. A variety of sources of information may be used
to obtain the information necessary to formulate a risk assessment.

Textbooks and databases are often difficult to interpret and apply to the
individual patient. When faced with a time-critical poisoning emergency,
a call to the poisons information centre is the most rapid mechanism to
obtain accurate information and individualised risk assessment.
The Australian Poisons Information Centre network comprises
centres located in Sydney, Perth, Brisbane and Melbourne that can be
accessed nation-wide by calling 131126. The New Zealand Poisons
Information Centre located in Dunedin is accessed by calling 0800-
POISON (0800 764 766). Trained poisons information specialists with a
background in pharmacy or medical science are familiar with accessing
information from computerised databases and other information sources.
They can assist in the identification of commercial products and their
constituents and in the formulation of a risk assessment, provided the
14
clinician is able to provide the basic dataset. Where necessary, medical
14
callers treating an acute poisoning case are referred to an on-call clinical

toxicologist who is able to offer more detailed individualised risk
TOXICOLOGY HANDBOOK
assessment and management advice.
Reference
Daly FF, Little M, Murray L. A risk assessment based approach to the management of
acute poisoning. Emergency Medicine Journal 2006; 23:396–399.
1.4 SUPPORTIVE CARE AND MONITORING

Following resuscitation and risk assessment, supportive care and
disposition planning can begin.
Poisoning morbidity and mortality usually result from the acute
effects of the toxin on the cardiovascular, central nervous or respiratory
systems. Support of these and other systems for the duration of the
intoxication will ensure a good outcome for the vast majority of acute
poisonings. Monitoring is essential to detect the progress of the
intoxication and the timing of institution, escalation and withdrawal of
supportive care and other measures.
An initial period of close observation in the emergency department is
usually appropriate. During this time the patient’s clinical status is
monitored closely to ensure that it correlates with the previous risk
assessment. If early complications are expected (e.g. decreased level of
consciousness requiring intubation in the following 2 hours),
preparations can be made to secure the airway as soon as the intoxication
declares itself, and before the patient is moved elsewhere. If unexpected
deterioration occurs at any time, the clinician’s priorities revert to
resuscitation prior to revising the risk assessment.
ERRNVPHGLFRVRUJ
The duration of observation depends on the agent(s) ingested, the

formulations involved (e.g. sustained-release preparations) and potential
complications. For example, patients with significant beta-blocker and
tricyclic antidepressant deliberate self-poisoning develop symptoms and
signs of major intoxication within 2–4 hours of ingestion. In contrast,
patients with sustained-release calcium channel blocker or valproic acid
deliberate self-poisoning may take 6–12 hours to develop signs of major
toxicity.
Disposition from the emergency department depends on the current
and expected clinical status of the patient. If specific complications are
anticipated, the chosen inpatient clinical area must be resourced to detect
and manage them.
The accuracy and skill of the initial management and risk assessment
are wasted if the subsequent plan of management is not documented and
communicated to the treating team. Good practice includes the
15
documentation of a comprehensive management plan that informs the
team looking after the patient of:
TOXICOLOGY HANDBOOK
1 Expected clinical course
2 Potential complications according to the individual risk assessment
3 Type of observation and monitoring required
4 End points that must trigger notification of the treating doctor or
further consultation
5 Management plans for agitation or delirium
6 Criteria for changing management
7 Provisional psychosocial risk assessment with contingency plan should
the patient attempt to abscond prior to formal psychosocial assessment.
The needs of the vast majority of patients can be met in the
emergency department, emergency observation unit or intensive care
unit. The emergency observation unit is appropriate for the ongoing
management of most acute poisonings, where the general supportive
measures outlined below can be provided.
Criteria for admission to an emergency observation unit following
acute poisoning include:
1 Clinical deterioration not anticipated
2 Adequate sedation achieved.
Criteria for admission to an intensive care unit following acute

poisoning include requirements for:
1 Airway control
2 Ventilation
3 Prolonged or invasive haemodynamic monitoring or support
4 Haemodialysis.
ERRNVPHGLFRVRUJ
TABLE 1.4.1 Supportive care measures

Airway
Intubation
Breathing
Supplemental oxygen
Ventilation
Circulation
Intravenous fluids
Inotropes
Control of hypertension
Extracorporeal membrane oxygenation
Sedation
Titrated IV benzodiazepines
Seizure control/prophylaxis
IV benzodiazepines
Metabolic
16 Ensuring normoglycaemia
Control of pH
16
Fluids and electrolytes

Renal function
TOXICOLOGY HANDBOOK
Adequate hydration
Haemodialysis
General
Nutrition
Respiratory toilet
Bladder care (indwelling catheter)
Prevention of pressure areas
Thromboembolism prophylaxis
Mobilisation as mental status changes resolve
1.5 INVESTIGATIONS
Investigations in acute poisoning are employed either as screening tests
or for specific purposes.
Screening refers to the performance of a medical evaluation and/or
diagnostic test in asymptomatic persons in the hope that early diagnosis
may lead to improved outcome. In the acutely poisoned patient,
screening tests aim to identify occult toxic ingestions for which early
specific treatment is indicated.
The recommended screening tests for acute poisoning are a 12-lead
electrocardiogram (ECG), a bedside blood glucose level (BGL) and a
serum paracetamol level (see Table 1.5.1).
The ECG is a readily available non-invasive tool that assists in the
identification of occult but potentially lethal cardiac conduction
abnormalities, such as those in tricyclic antidepressant cardiotoxicity.
The bedside BGL is used to detect hypoglycaemia that may be
missed, particularly in the patient with altered mental status due to other
ERRNVPHGLFRVRUJ
TABLE 1.5.1 Screening tests
12-lead ECG
Rate
Rhythm
PR interval
QRS interval
QT interval
Dominant R wave in aVR
Bedside BGL
Serum paracetamol level
drug effects. It is usually performed during the initial resuscitation and

assessment phase of any poisoned patient with altered mental status.
Paracetamol is a ubiquitous analgesic in the western world.
Deliberate self-poisoning with paracetamol is common, comprising up to
17
15% of adult poisoning presentations in Australasia. Life-threatening
paracetamol poisoning may be occult in the early stages but progression
to fulminant hepatic failure and death can be prevented by timely
TOXICOLOGY HANDBOOK
administration of N-acetylcysteine. Although a thorough cost–benefit
analysis has never been performed, it is postulated that the cost of
several thousand serum paracetamol measurements is offset by the
detection of one potentially preventable paracetamol-related death or
liver transplant. For this reason, it is advisable to screen for paracetamol
in all cases of known or suspected acute deliberate self-poisoning.
Screening is particularly important where altered mental status precludes
obtaining an ingestion history directly from the patient.
The screening paracetamol level may be performed at presentation
and does not need to be delayed until 4 hours after ingestion. A non-
detectable paracetamol level more than 1 hour after ingestion excludes
significant paracetamol ingestion and further paracetamol levels are not
required.
If paracetamol poisoning is suspected after the initial risk assessment,
then a screening paracetamol level is not required. Instead, a timed
paracetamol level should be performed as soon as possible after 4 hours
post-ingestion as an additional risk assessment tool.
Serum salicylate and tricyclic antidepressant assays have been
advocated as routine screening tests. Salicylate poisoning is now
relatively uncommon in Australasia. Significant acute intoxication is
associated with an easily-recognised pattern of symptoms and acid–base
disturbances and is rarely occult. Therefore, routine screening for
salicylate in patients without symptoms or signs of salicylism does not
comply with the rationale for screening and should not be performed.
Serum tricyclic antidepressant levels correlate with complications and
outcome following acute poisoning. However, the major complications
ERRNVPHGLFRVRUJ
of tricyclic antidepressant poisoning usually occur within 2–4 hours of
ingestion. The 12-lead ECG, correlated to the patient’s clinical status,

reflects target organ effects more accurately and is the preferred
screening test.
Many poisoned patients are young and have few medical
co-morbidities. After appropriate risk assessment and the institution of
supportive care they may require no further investigation beyond the
screening ECG, bedside BGL and serum paracetamol measurement. In a
young and otherwise healthy patient presenting with normal mental
status and vital signs, additional tests such as electrolytes, full blood
picture, liver function tests and coagulation studies are not routinely
indicated.
Other investigations are ordered selectively where it is anticipated
that the results will assist risk assessment or management. Potential
indications for specific tests in the acute poisoning patient are shown in
18
Table 1.5.2.
18
For most patients and poisonings, the risk assessment and subsequent
clinical course dictate management decisions. Drug concentrations do
TOXICOLOGY HANDBOOK
not usually assist decision making. Some of the few agents where serum
levels assist in risk assessment or management decisions are shown in
Table 1.5.3.
Qualitative urine screens for drugs of abuse (e.g. opioids,
benzodiazepines, amphetamines, cocaine, barbiturates and cannabinoids)
rarely alter the management of the acutely poisoned patient. Patients
with acute intoxication with one or more of these agents may be
TABLE 1.5.2 Indications for other investigations
Refine risk assessment or prognosis

Exclude or confirm an important differential diagnosis
Exclude or confirm an important specific poisoning
Exclude or confirm a complication that requires specific management
Establish an indication for antidote administration
Establish an indication for institution of enhanced elimination
Monitor response to therapy or define an end point for a therapeutic
intervention
TABLE 1.5.3 Useful drug levels that may assist risk assessment or
management in specific settings
Carbamazepine Lithium Salicylate

Digoxin Methanol Theophylline
Ethanol Methotrexate Valproic acid
Ethylene glycol Paracetamol
Iron Phenobarbitone
ERRNVPHGLFRVRUJ
managed according to their clinical presentation. False positives and

negatives occur. A positive result from a patient without corresponding
symptoms of intoxication rarely alters acute medical management.
References
Ashbourne JF, Olson KR, Khayam-Bashi H. Value of rapid screening for
acetaminophen in all patients with intentional drug overdose. Annals of
Emergency Medicine 1989; 18(10):1035–1038.
Sporer KA, Khayam-Bashi H. Acetaminophen and salicylate serum levels in patients
with suicidal ingestion or altered mental status. American Journal of Emergency
Medicine 1996; 14(5):443–446.
1.6 GASTROINTESTINAL DECONTAMINATION

Doctors have long directed great effort into attempts at gastrointestinal
decontamination following ingestion of toxic substances. They have 19
employed a variety of methods (see Table 1.6.1) in the reasonable
expectation that, by reducing the dose absorbed, they will also reduce the
TOXICOLOGY HANDBOOK
subsequent severity and duration of clinical toxicity. Unfortunately, the
tendency has been to overestimate the potential benefits while
underestimating the potential hazards of gastrointestinal decontamination
procedures. These procedures do not provide significant benefit when
applied to unselected deliberate self-poisoned patients and are no longer
considered routine.
The theoretical benefits of gastrointestinal decontamination in
selected poisonings have not been evaluated. The decision to
decontaminate is one of clinical judgement in which the potential
benefits are weighed against the potential risks and the resources
required to perform the procedure (see Figure 1.6.1 and Table 1.6.2).
Employing this rationale, gastrointestinal decontamination is reserved
for cases where the risk assessment predicts severe or life-threatening
toxicity and where supportive care or antidote treatment alone is
insufficient to ensure a satisfactory outcome. There should be reasonable
grounds to believe that a significant amount of agent remains unabsorbed
and is amenable to removal by the selected procedure. This requires
some knowledge of the absorption kinetics of the agent(s) involved. For
most ingested agents, absorption is virtually complete within 1 hour.
TABLE 1.6.1 Methods of gastrointestinal decontamination
● Induced emesis (syrup of ipecac)

● Gastric lavage
● Activated charcoal
● Whole bowel irrigation
ERRNVPHGLFRVRUJ
FIGURE 1.6.1 Gastrointestinal decontamination triangle
Risk Assessment
DECONTAMINATION
Given current clinical

What are the potenal
status, what are potenal
benefits to outcome?
adverse effects?
20 Source: Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005;

20
1:59–60.
TOXICOLOGY HANDBOOK
TABLE 1.6.2 Gastrointestinal decontamination: risk–benefit analysis
Potential benefits Potential risks

● Improved clinical outcome ● Pulmonary aspiration
(morbidity and mortality) ● Gastrointestinal complications
● More benign clinical course — Bowel obstruction
requiring lower level of — Perforation
supportive care ● Distraction of staff from
● Reduced need for other resuscitation and supportive
potentially hazardous care priorities
interventions or expensive ● Diversion of departmental
antidotes resources for performance of
● Reduced hospital length of stay procedure
Gastrointestinal decontamination is never performed to the detriment

of basic resuscitation or supportive care. To avoid pulmonary aspiration,
the procedure is not performed without first securing the airway in a
patient with a depressed level of consciousness or in whom the risk
assessment indicates a potential for imminent seizures or decline in
conscious state.
INDUCED EMESIS (SYRUP OF IPECAC)

Emptying the stomach by inducing emesis has a long tradition in clinical
toxicology but has recently been all but abandoned. Administration of
syrup of ipecac was for many years routinely recommended for home
use following accidental paediatric ingestions with the intention of
ERRNVPHGLFRVRUJ
reducing the time to decontamination and the need for hospital referral.

This preparation contains powerful plant-derived emetics and, when
administered at the recommended dose, reliably induces vomiting via
central and peripheral mechanisms. The mean time from administration
to vomiting is 18 minutes. It is now clear that the amount of toxin
removed is highly variable and decreases rapidly with time to the point
that it is negligible by 1 hour. Syrup of ipecac-induced vomiting renders
subsequent administration of activated charcoal more difficult. The
potential benefits of syrup of ipecac theoretically outweigh the risks
when it is administered promptly after ingestion of an agent in a dose
likely to cause significant toxicity, which does not involve rapid onset of
depressed level of consciousness or seizures and where activated
charcoal is not readily available or known not to bind to the agent. Such
a scenario arises so infrequently that emergency departments no longer
stock syrup of ipecac and poisons information centres no longer advise it
21
to be kept in homes with small children.
Technique
•
TOXICOLOGY HANDBOOK
Give 15 mL (children) or 15–30 mL (adults) with a glass of water.
• If vomiting has not occurred within 30 minutes the dose may be
repeated.
Contraindications
• Non-toxic ingestion
• Dose ingested known to be sub-toxic
• Seizures or decreased level of consciousness
• Risk assessment indicating potential for seizures or decreased level
of consciousness within the next few hours
• Activated charcoal available within 1 hour and known to bind agent
• Infants <12 months of age
• Corrosive ingestion
• Hydrocarbon ingestion
Potential complications
• Prolonged vomiting (10–20% vomit for more than 1 hour)
• Diarrhoea (20–30%)
• Pulmonary aspiration if decreased mental status or seizures
• Physical injuries secondary to vomiting (rare)
— Mallory-Weiss tear
— Pneumomediastinum
— Gastric perforation
GASTRIC LAVAGE
This technique attempts to empty the stomach of toxic substances by the
sequential administration and aspiration of small volumes of fluid from
ERRNVPHGLFRVRUJ
the stomach via an orogastric tube. This previously widely favoured
method of gastrointestinal decontamination has now been all but

abandoned and few emergency department staff remain experienced in
its use.
The amount of toxin removed by gastric lavage is unreliable and
negligible if performed after the first hour. It does not confer any clinical
benefit when performed routinely on unselected patients presenting to
the emergency department following deliberate self-poisoning. There are
few situations where the expected benefits of this procedure might be
judged to exceed the risks involved and where administration of charcoal
would not be expected to provide equal or greater efficacy of
decontamination.
Technique
• This procedure is performed in a resuscitation bay.
22
• Do not perform in any patient with an impaired level of
22
consciousness unless the airway is protected by a cuffed endotracheal

tube.
TOXICOLOGY HANDBOOK
• Position the patient in the left decubitus position with 20° head down.
• Measure the length of tube required to reach the stomach externally
before beginning the procedure.
• Pass a large bore 36–40 G lubricated lavage tube extremely gently
down the oesophagus. Stop if any resistance occurs.
• Confirm tube position by aspirating gastric contents and auscultating
for insufflated air at the stomach.
• Administer a 200-mL aliquot of warm tap water or normal saline into
the stomach via the funnel and lavage tube.
• Drain the administered fluid into a dependent bucket held adjacent to
the bed.
• Repeat administration and drainage of fluid aliquots until the effluent
is clear.
• Activated charcoal 50 g may be administered via the tube once
lavage is complete.
Contraindications
• Initial resuscitation incomplete
• Risk assessment indicating good outcome with supportive care and
antidote therapy alone
• Unprotected airway where there is a decreased level of consciousness
or risk assessment indicating potential for this complication during
the procedure
• Small children
• Hydrocarbon ingestion
ERRNVPHGLFRVRUJ

• Pulmonary aspiration
• Hypoxia
• Laryngospasm
• Mechanical injury to the gastrointestinal tract
• Water intoxication (especially in children)
• Hypothermia
• Distraction of staff from resuscitation and supportive care priorities
SINGLE-DOSE ACTIVATED CHARCOAL

Activated charcoal (AC) is produced by the super-heating of distilled
wood pulp. The resulting fine porous particles are suspended in water or
sorbitol prior to oral or nasogastric administration. The enormous surface
area provided by these particles reversibly adsorbs most ingested toxins
reducing further absorption from the gastrointestinal tract. 23
Oral AC is generally the preferred method of gastrointestinal
decontamination. Human volunteer studies confirm that oral AC reduces
TOXICOLOGY HANDBOOK
drug absorption when given up to 4 hours after ingestion but is most
effective when given immediately after ingestion. However, oral AC
does not improve clinical outcome when applied to unselected patients
with self-poisoning and should not be regarded as routine. Oral AC is
most likely to benefit a subgroup of patients with severe poisoning in
whom it may reduce the length of hospital stay, level of supportive care
required, need for administration of antidotes or utilisation of enhanced
elimination techniques. Overall, oral AC is indicated where it is likely
that toxin remains in the gastrointestinal tract, and where the potential
benefits outweigh the potential risks. It is reasonable to routinely
administer oral AC following intubation to unconscious patients who
have ingested pharmaceutical agents as the risk–benefit analysis is
almost always in favour of administration. By contrast, the potential
benefits rarely justify administration of oral AC to the uncooperative
conscious patient.
There are no data to support the use of AC in sorbitol or other
cathartic agents over AC in water.
• Mess
• Pulmonary aspiration of AC
• Direct administration into lung via misplaced nasogastric tube
(potentially fatal)
• Impaired absorption of subsequently administered oral antidotes or
other therapeutic agents
• Corneal abrasions
ERRNVPHGLFRVRUJ
TABLE 1.6.3 Agents poorly bound to activated charcoal
Hydrocarbons and alcohols Metals Corrosives
Ethanol Lithium Acids

Isopropyl alcohol Iron Alkalis
Ethylene glycol Potassium
Methanol Lead
Arsenic
Mercury
• Distraction of attending staff from resuscitation and supportive care

priorities
Contraindications
• Initial resuscitation incomplete
24
• Non-toxic ingestion
•
24
Sub-toxic dose
• Uncooperative patient (relative contraindication)
TOXICOLOGY HANDBOOK
• Risk assessment indicating good outcome with supportive care and

antidote therapy alone
• Decreased level of consciousness, delirium or poor cooperation
(unless airway protected by endotracheal intubation)
• Risk assessment suggesting potential for imminent onset of seizures
or decreased level of consciousness.
• Agent not bound to AC (see Table 1.6.3)
Note: Ileus is not a contraindication to single-dose AC.
Technique
• Give 50 g (adults) or 1 g/kg (children) as a single oral dose placed in
a cup for self-administration.
• Mixing with ice cream improves palatability for children.
• In the intubated patient, AC may be given via oro- or nasogastric
tube after tube placement is confirmed on chest X-ray.
Note: If mental status precludes self-administration, AC is withheld
until the patient is intubated if and when this becomes clinically
necessary. The decision to intubate is based on standard criteria. Only in
very rare circumstances does the risk assessment justify intubation
specifically for the purpose of facilitating administration of AC.
WHOLE BOWEL IRRIGATION

This labour-intensive form of gastrointestinal decontamination attempts
to cleanse the entire bowel by administering large volumes of osmotically
ERRNVPHGLFRVRUJ
TABLE 1.6.4 Whole bowel irrigation potentially useful
● Iron overdose >60 mg/kg

● Slow-release potassium chloride ingestion >2.5 mmol/kg
● Life-threatening slow-release verapamil or diltiazem ingestions
● Symptomatic arsenic trioxide ingestion
● Lead ingestion
● ‘Body packers’ (see Chapter 2.17: Body packers and stuffers)
balanced polyethylene glycol electrolyte solution (PEG-ELS). It is rarely

performed because risk–benefit analysis reserves this intervention for
life-threatening ingestions of sustained-release or enteric-coated
preparations; or agents that do not bind to charcoal and where good
clinical outcome is not expected with supportive care and antidote
administration and the patient presents before established severe toxicity
(see Table 1.6.4). 25
Whole bowel irrigation has been performed on unconscious
ventilated patients but this is hazardous as fluid may pool in the
TOXICOLOGY HANDBOOK
oropharynx and flow past the tube cuff to produce pulmonary aspiration.
• Nausea, vomiting and abdominal bloating
• Non-anion gap metabolic acidosis
• Distraction from resuscitation and supportive care priorities
• Delayed retrieval to a hospital offering definitive care
Contraindications
• Risk assessment suggesting good outcome can be assured with
supportive care and antidote therapy
• Uncooperative patient
• Inability to place a nasogastric tube
• Uncontrolled vomiting
• Risk assessment suggesting potential for decreased conscious state or
seizure in the subsequent 4 hours
• Ileus or intestinal obstruction
• Intubated and ventilated patient (relative contraindication)
Technique
• Assign a single nurse to carry out the procedure (this is a full-time
job for up to 6 hours).
• Obtain sufficient supplies of PEG-ELS and make up the solution as
directed.
• Place nasogastric tube and confirm position on chest X-ray.
ERRNVPHGLFRVRUJ
• Give activated charcoal 50 g (children 1 g/kg) via the nasogastric
tube unless agent does not bind to AC.

• Administer PEG solution via the nasogastric tube at 2 L/hour by
continuous infusion (children 25 mL/kg/hour).
• Administer metoclopramide to minimise vomiting and enhance
gastric emptying.
• Position patient on a commode if possible to accommodate explosive
diarrhoea.
• Continue irrigation until the effluent is clear. This may take up to 6
hours.
• Cease whole bowel irrigation if abdominal distension or loss of
bowel sounds is noted.
• Abdominal X-ray is useful to assess effectiveness of decontamination
of radio-opaque substances such as iron and potassium salts.
26 • Expelled packages may be counted in body packers.
26
References
American Academy of Clinical Toxicology and the European Association of Poison
TOXICOLOGY HANDBOOK
Centres and Clinical Toxicologists. Position paper: whole bowel irrigation.

Clinical Toxicology 2004; 42:843–854.
American Academy of Clinical Toxicology and the European Association of Poison
Centres and Clinical Toxicologists. Position paper: single-dose activated charcoal.
Bailey B. Gastrointestinal decontamination triangle. Clinical Toxicology 2005;
1:59–60.
Benson BE, Hoppu K, Troutman WG et al. Position paper update: gastric lavage for
gastrointestinal decontamination. Clinical Toxicology 2013; 51:140–146.
Hojer J, Troutman WG, Hoppu K et al. Position paper update: ipecac syrup for
gastrointestinal decontamination. Clinical Toxicology 2013; 51:134–139.
Isbister GK, Pavan Kumar VV. Indications for single dose activated charcoal
administration. Current Opinion in Critical Care 2011; 17:351–357.
1.7 ENHANCED ELIMINATION

Techniques of enhanced elimination (see Table 1.7.1) are employed to
increase the rate of removal of an agent from the body with the aim of
reducing the severity and duration of clinical intoxication.
These interventions are only indicated if it is thought they will
reduce mortality, length of stay, complications or the need for other more
invasive interventions. In practice, these techniques are useful in the
treatment of poisoning by only a few agents that are characterised by:
• Severe toxicity
• Poor outcome despite good supportive care/antidote administration
• Slow endogenous rates of elimination
• Suitable pharmacokinetic properties.
ERRNVPHGLFRVRUJ
TABLE 1.7.1 Techniques of enhanced elimination and amenable agents
Multiple-dose activated charcoal Haemodialysis and haemofiltration
Carbamazepine Carbamazepine
Dapsone Lithium
Phenobarbitone Metformin lactic acidosis
Quinine Potassium
Theophylline Salicylate
Urinary alkalinisation Theophylline
Phenobarbitone Toxic alcohols
Salicylate Valproic acid
Charcoal haemoperfusion
Theophylline
Accurate risk assessment allows early identification of those patients

who may benefit from enhanced elimination and institution of the 27
intervention before severe life-threatening intoxication develops. Some
of these techniques require specialised equipment and staff and early
identification of candidates facilitates the timely communication,
TOXICOLOGY HANDBOOK
planning and transport necessary to ensure a good outcome.
The final decision as to whether to initiate a technique of enhanced
elimination depends on a risk–benefit analysis in which the expected
benefits of the procedure are balanced against the resource utilisation and
risks associated with the procedure.
Techniques of enhanced elimination are never carried out to the
detriment of resuscitation, good supportive care, decontamination and
antidote treatment.
Once the decision to initiate a technique of enhanced elimination is
made, it is important to establish pre-defined clinical or laboratory end
points for therapy.
MULTIPLE-DOSE ACTIVATED CHARCOAL (MDAC)

Rationale
Repeated administration of oral activated charcoal progressively fills the
entire gut lumen with charcoal. This has the potential to enhance drug
elimination in two ways:
• Interruption of enterohepatic circulation

— A number of drugs are excreted in the bile and then
reabsorbed from the distal ileum. Charcoal in the small
intestine binds drug and prevents reabsorption thus enhancing
elimination.
— This is only significant if a drug not only undergoes entero-
hepatic circulation but also has a relatively small volume of
distribution.
ERRNVPHGLFRVRUJ
• Gastrointestinal dialysis
— Drug passes across the gut mucosa from a relatively high

concentration in the intravascular compartment to a low
concentration in the gut lumen, which is maintained by
continuing adsorption to charcoal.
— This is only effective if the drug is a relatively small molecule,
lipid soluble, has a small volume of distribution and low protein
binding.
Indications
Enhanced elimination by this technique has been proposed as clinically
useful in the following scenarios:
• Carbamazepine coma
— Most common indication for MDAC
28 — Used in the expectation that enhanced elimination will reduce
duration of ventilation and length of stay in intensive care
28
• Phenobarbitone coma
TOXICOLOGY HANDBOOK
— Rare
— Used in the expectation that enhanced elimination will reduce
duration of ventilation and length of stay in intensive care
• Dapsone overdose with methaemoglobinaemia
— Very rare
— MDAC may enhance elimination of dapsone and reduce the
duration of severe prolonged methaemoglobinaemia
• Quinine overdose
— Although MDAC might enhance drug elimination, good outcome
can be expected with aggressive supportive care
• Theophylline overdose
— Attempts at enhanced elimination with MDAC should never
delay more effective elimination techniques (haemodialysis)
following life-threatening overdose.
Contraindications
• Decreased level of consciousness or anticipated decreased level of
consciousness without prior airway protection
• Bowel obstruction
Although rare in carefully selected patients, they may include:
• Vomiting (30%)
• Charcoal aspiration, especially if there is decreased mental status or
seizures
• Constipation
ERRNVPHGLFRVRUJ
• Charcoal bezoar formation, bowel obstruction, bowel perforation (rare)

• Corneal abrasion
• Distraction of attending staff from resuscitation and supportive care
priorities.
Technique
• Give an initial dose of activated charcoal 50 g (adults) or 1 g/kg
(children) PO.
• Give repeat doses of 25 g (0.5 g/kg in children) every 2 hours.
• In the intubated patient, activated charcoal is given via oro- or
nasogastric tube after tube placement has been confirmed on chest
X-ray.
• Check for bowel sounds and high nasogastric aspirates prior to
administration of each dose.
• Cease further administration if bowel sounds are inaudible or
nasogastric aspirates of high volume.
29
• Reconsider the indications and clinical end points for therapy every 6
hours. MDAC should rarely be required beyond 6 hours.
TOXICOLOGY HANDBOOK
URINARY ALKALINISATION
Rationale
The production of an alkaline urine pH promotes the ionisation of acidic
drugs and prevents reabsorption across the renal tubular epithelium, thus
promoting excretion in the urine. For this method to be effective the
drug must be filtered at the glomerulus, have a small volume of
distribution and be a weak acid.
Indications
Only two drugs of significance in clinical toxicology have the required
pharmacokinetic properties for this method to be of interest in
management of poisoning.
• Salicylate overdose
— Salicylates are normally eliminated by hepatic metabolism and
are not readily excreted in acidic urine. In overdose, metabolism
is saturated and elimination half-life greatly prolonged.
— Urinary alkalinisation greatly enhances elimination and is
indicated in any symptomatic patient in an effort to reduce the
duration and severity of symptoms or to avoid progression to
severe poisoning and the need for haemodialysis.
— Severe established salicylate toxicity indicates immediate
haemodialysis rather than a trial of urinary alkalinisation.
— Note: Not generally useful in chronic salicylate toxicity due to
co-morbidities.
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— May be attempted in an effort to reduce duration of coma and

length of stay in intensive care.
— Not first-line as MDAC is a superior technique of enhancing
elimination.
Contraindications
• Fluid overload
Complications
• Alkalaemia (usually well-tolerated)
— Fluid overload
• Hypokalaemia
• Hypocalcaemia (not usually clinically significant)
30 Technique
•
30
Correct hypokalaemia if present (it is difficult to alkalinise the urine

in the presence of systemic hypokalaemia).
TOXICOLOGY HANDBOOK
• Give 1–2 mmol/kg sodium bicarbonate IV bolus.

• Commence infusion of 150 mmol sodium bicarbonate in 850 mL 5%
dextrose at 250 mL/hour.
• 20 mmol of potassium chloride may be added to infusion to maintain
normokalaemia.
• Monitor serum bicarbonate and potassium at least every 4 hours.
• Regularly dipstick urine and aim for urinary pH >7.5.
• Continue until clinical and laboratory evidence of toxicity is
resolving.
EXTRACORPOREAL TECHNIQUES OF ELIMINATION

A number of such techniques have been used to enhance elimination of
toxins including:
• Haemodialysis
— Intermittent
— Continuous
• Haemofiltration
• Haemoperfusion
• Plasmapheresis
• Exchange transfusion.
All of the above techniques are invasive and require specialised
staff, equipment and monitoring, and may be associated with
significant complications. For these reasons they are reserved for
life-threatening poisonings where a good outcome cannot be achieved
ERRNVPHGLFRVRUJ
by other means, including aggressive supportive care and antidote

administration.
Haemodialysis effectively enhances elimination of any drug that is a
small molecule, has a small volume of distribution, rapid redistribution
from tissues and plasma and slow endogenous elimination. Clinical
situations that involve life-threatening poisoning with agents fulfilling
these criteria include:
• Toxic alcohol poisoning

— Methanol
— Ethylene glycol
• Theophylline poisoning
• Severe salicylate intoxication
— Chronic intoxication with altered mental status
— Late-presentation acute overdose with established severe toxicity
• Severe chronic lithium intoxication 31
• Metformin lactic acidosis
•
TOXICOLOGY HANDBOOK
Massive valproate overdose
• Massive carbamazepine overdose
• Potassium salt overdose with life-threatening hyperkalaemia.
Precise clinical indications for extracorporeal elimination in each of
these important poisonings are discussed in the relevant sections of
Chapter 3. The decision to institute extracorporeal elimination should be
made early as soon as the risk assessment indicates potential lethality. In
general, intermittent dialysis achieves greater clearance rates than
continuous haemodialysis or haemofiltration techniques and is preferred
where available. Facilities for charcoal haemoperfusion are not available
in most centres.
References
Anonymous. Position Statement and Practice Guidelines on the use of multi-dose
activated charcoal in the treatment of acute poisoning. Clinical Toxicology 1999;
37(6):731–751.
Dorrington CL, Johnson DW, Brant R. The frequency of complications associated with
the use of multiple-dose activated charcoal. Annals of Emergency Medicine 2003;
41(3):370–377.
Ouellet GI, Bouchard J, Ghannoum M, Decker BS. Available extracorporeal treatments
for poisoning: overview and limitations. Seminars in Dialysis 2014; doi: 10.1111/
sdi.12238. [Epub ahead of print].
Pond SM, Olson KR, Osterloh JD et al. Randomised study of the treatment of
phenobarbital overdose with repeated doses of activated charcoal. Journal of the
American Medical Association 1984; 251:3104–3108.
Proudfoot AT, Krenzelok EP, Vale JA. Position paper on urine alkalinization. Journal
of Toxicology Clinical Toxicology 2004; 42:1–26.
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1.8 ANTIDOTES
Antidotes are drugs that correct the effects of poisoning. Only a few
antidotes exist and many are used only rarely. Specific antidotes likely to
be used in clinical practice are discussed in Chapter 4 of this book.
Like all pharmaceuticals, antidotes have specific indications,
contraindications, optimal administration methods, monitoring
requirements, appropriate therapeutic end points and adverse effect
profiles.
The decision to administer an antidote to an individual patient is
based upon a risk–benefit analysis. An antidote is administered when the
potential therapeutic benefit is judged to exceed the potential adverse
effects, cost and resource requirements. An accurate risk assessment
combined with pharmaceutical knowledge of the antidote is essential to
32 clinical decision making.
Many antidotes are rarely prescribed, expensive and not widely
32
stocked. Planning of stocking, storage, access, monitoring, training and

TOXICOLOGY HANDBOOK
protocol development are essential components of rational antidote use.

It is often appropriate for stocking to be coordinated on a regional basis
in association with regional policies concerning the treatment of
poisoned patients. It is frequently cheaper and safer to transport an
antidote to a patient rather than vice versa.
Reference
Dart RC, Borrow SW, Caravati EM et al. Expert consensus guidelines for stocking of
antidotes in hospitals that provide emergency care. Annals of Emergency
Medicine 2009: 54:386–394.
1.9 DISPOSITION
A medical disposition is required for all patients who present with
poisoning or potential exposure to a toxic substance. Those who have
deliberately self-poisoned also require psychiatric and social review. A
risk-assessment-based approach to the management of acute poisoning
allows early planning for appropriate medical and psychosocial
disposition. Patients must be admitted to an environment capable of
providing an adequate level of monitoring and supportive care and, if
appropriate, where staff and resources are available to undertake
decontamination, enhanced elimination techniques or administration of
antidotes.
Early risk assessment in the pre-hospital setting, usually by poisons
information centre staff, often allows non-intentional exposures to be
observed outside of the hospital environment. For those that present to
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hospital, it minimises the duration and intensity of monitoring. Frequently,

patients can be ‘cleared’ for medical discharge directly from the
emergency department immediately following assessment or following a
few hours of observation. No arrangements for admission to hospital need
to be made unless unexpected signs or symptoms of toxicity develop.
At other times the risk assessment will indicate the need for ongoing
observation, supportive care or the need for specific enhanced elimination
techniques or antidote administration. Under these circumstances, the
patient must be admitted to an environment capable of providing a level
of care appropriate for the anticipated clinical course. In many hospitals,
this is now the emergency observation unit rather than the general
medical ward. Where ongoing airway control, ventilation or advanced
haemodynamic support is required, admission to an intensive care unit is
appropriate.
EMERGENCY OBSERVATION UNITS 33

Emergency observation units (EOUs) have been established in many
emergency departments in Australasia and elsewhere. These units vary in
TOXICOLOGY HANDBOOK
capacity, design and staffing. Ideally, they are located adjacent to
emergency departments, staffed by emergency doctors and provide
short-term focused goal-oriented care. They have been remarkably
successful in:
• Streamlining treatment in suitable conditions

• Reducing total bed days
• Increasing patient satisfaction
• Reducing inappropriate discharges and litigation.
TOXICOLOGY PATIENTS IN THE EMERGENCY OBSERVATION UNIT

In most hospitals where EOUs are established, the units appear to provide
an ideal environment for the management of acute poisoning beyond the
initial assessment and monitoring phase. Advantages of using the EOU to
admit toxicology patients include the ready availability of appropriate
resources, staff and training; 24-hour availability of experienced medical
staff; an open-plan environment that facilitates observation; and an
emergency department ethos that is geared towards rapid assessment and
disposition. Adequate resources must be dedicated to the EOU,
particularly medical, nursing, psychiatric and social services.
Ideal design features and staffing that facilitate the management of
toxicology patients in the EOU include:
• Central nursing stations with clear vision of all areas

• An environment that protects from self-harm
• Secure entrances
• Dedicated areas for private interviews
ERRNVPHGLFRVRUJ
• Dedicated social work, drug and alcohol, plus outpatient liaison
services
• Appropriate monitors ± telemetry
• Dedicated resuscitation equipment
• Duress alarms
• Appropriate staff, skills and equipment
• Appropriate 24/7/365 senior staff coverage
• Dedicated psychiatric services
• Nurse–patient ratios appropriate for the acuity of patients (e.g. 1 : 4
for monitored ‘step-down’ patients; 1 : 8 for non-monitored general
patients).
Criteria need to be developed for admission to the EOU following
acute poisoning. Such criteria might include:
34 • Cardiac monitoring not required (but this can be provided in some

EOUs)
•
34
Adequate sedation in cases of delirium

• Deterioration not anticipated (based on accurate risk assessment and
TOXICOLOGY HANDBOOK
initial period of observation in the emergency department).

Admission of toxicology patients to the EOU helps counter several
of the difficulties encountered when poisoned patients are admitted to
other areas of the hospital:
• Admissions scattered all over the hospital

• Less experienced nursing staff
• Poor availability of medical staff
• Frequent security incidents/absconding patients
• Most clinicians managing patients on general medical wards are
junior and have no formal or informal training in clinical toxicology
• Longer admissions.
RETRIEVAL OF THE POISONED PATIENT
Usually, the initial receiving hospital is adequately resourced to provide
an acceptable level of supportive care, monitoring and therapy for the
poisoned patient. If this is not the case, transfer is necessary. Risk
assessment ensures that the need to transfer is recognised early so that
appropriate planning and consultation takes place in an effort to ensure
as smooth a retrieval as possible (see Table 1.9.1). Poisoning is unusual
in that transfer frequently takes place during the most severe phase of
the illness.
Resuscitation
The need to retrieve a patient to another centre should not distract
attending staff from resuscitation and supportive care priorities. Attention
ERRNVPHGLFRVRUJ
TABLE 1.9.1 Principles of retrieval of the poisoned patient
● Risk assessment is vital

● Identify patients who may need retrieval to another hospital as soon as
possible
● Patients should only be retrieved for specific clinical indications
● Recognise that transport may occur during the worst phase of the
intoxication
● Consider bringing expertise and resources to the patient, rather than
vice versa
● Assess, manage and stabilise potential resuscitation and supportive
care priorities prior to transfer
● Ensure that transport does not lead to an interval of lower level of care
● Transport to a centre capable of definitive care
to airway, breathing and circulation ensure an optimum outcome in the 35

majority of cases. Whenever possible, the patient should be stabilised
before retrieval begins. Interventions such as intubation, ventilation,
initial resuscitation of hypotension, cessation of seizures, assessment of
TOXICOLOGY HANDBOOK
blood glucose and management of hyperthermia are completed before a
patient is placed in the transport vehicle, where further assessment and
detailed management are often impossible. If the referring team does not
possess the necessary skills or resources to complete these resuscitation
and stabilisation tasks adequately, this should be communicated to the
receiving and retrieval teams, so that these resources can be brought to
the patient.
Transport
As transport usually occurs during the most severe phase of the
poisoning, the patient should never be subjected to an interval of a lower
level of care during the transfer. Consideration of the mode and staffing
of transport takes this into account.
Planning
Planning is required to ensure that any potential complications are
identified and managed in a proactive fashion. Thus, if coma requiring
intubation and ventilation is anticipated in the next few hours (e.g.
controlled-release carbamazepine), early intubation and ventilation should
occur prior to transfer. Similarly, if significant hypotension is expected
(e.g. calcium channel blockers), appropriate monitoring, intravenous
access and resuscitation resources should be ready prior to transfer.
Communication
Communication is vital. Retrieval is always to a higher level of care.
Thus, transport must occur to a facility with appropriate resources to
ERRNVPHGLFRVRUJ
manage the potential complications identified by the risk assessment. For
example, if haemodialysis may be required (e.g. theophylline or

salicylate poisoning), the patient must be transported to a facility capable
of instituting this intervention at short notice. Ideally, communication
should include the team of clinicians who will ultimately manage the
patient. Consultations with other specialist teams (e.g. paediatricians,
intensivists or clinical toxicologists) may also occur to assist the process.
This improves continuity of care and decreases the inefficiencies and
errors that may be associated with multiple handovers.
Antidotes
If an antidote is likely to definitively treat the patient and render them
stable (e.g. N-acetylcysteine; digoxin-specific antibodies), it is preferable
to transfer the antidote to the patient, start treatment, then move the
patient only if necessary.
36
Psychosocial assessment
36
Most episodes of acute poisoning represent an exacerbation of an

TOXICOLOGY HANDBOOK
underlying psychosocial disorder and the final disposition of the patient

is made in this context. All patients with deliberate self-poisoning should
undergo psychosocial assessment prior to discharge. Ideally, this process
begins before the medical treatment of the poisoning is complete so that
final disposition is facilitated.
References
Daly FFS, Little M, Murray L. A risk assessment based approach to the management
of acute poisoning. Emergency Medicine Journal 2006; 23:396–399.
Ross MA, Graff LG. Principles of observation medicine. Emergency Medicine Clinics
of North America 2001; 19(1):1–17.
Warren J, Fromm RE, Orr RA, et al. Guidelines for the inter- and intrahospital
transport of critically ill patients. Critical Care Medicine 2004; 32:256–262.
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CHAPTER 2
SPECIFIC CONSIDERATIONS
2.1 Approach to snakebite 38

2.2 Approach to mushroom poisoning 45
2.3 Approach to plant poisoning 52
2.4 Coma 58
2.5 Hypotension 62
2.6 Seizures 64
2.7 Delirium and agitation 65
2.8 Serotonin syndrome 70
2.9 Anticholinergic syndrome 76
2.10 Cholinergic syndrome 80
2.11 Neuroleptic malignant syndrome 83
2.12 Alcohol use disorder 89
2.13 Amphetamine use disorder 98
2.14 Opioid use disorder 99
2.15 Sedative-hypnotic use disorder 103
2.16 Solvent abuse 106
2.17 Body packers and stuffers 110
2.18 Osmolar gap 113
2.19 Acid–base disorders 116
2.20 The 12-lead ECG in toxicology 121
2.21 Poisoning during pregnancy and lactation 127
2.22 Poisoning in children 128
2.23 Poisoning in the elderly 134
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2.1 APPROACH TO SNAKEBITE
See also specific sections in Chapter 5: Black snake, Brown snake, Death
adder, Sea snake, Taipan, Tiger snake group.
Definite or suspected snakebite is a regular presentation to
emergency departments in most parts of Australia. In contrast, severe

envenoming is a rare but potentially lethal presentation. Few clinicians
have the opportunity to develop sufficient clinical experience to feel
comfortable managing envenoming.
Snakebite is a time-critical emergency presentation and a simple but
robust approach is required to ensure adequate treatment should
envenoming develop (see Table 2.1.1).
The clinical effects of the medically important Australian snakes are
summarised in Table 2.1.2.
38 RISK ASSESSMENT
Once it is appreciated that snakebite is a possibility, the risk assessment
38
is straightforward: there is a risk of life-threatening envenoming and a

TOXICOLOGY HANDBOOK
formal process must begin to exclude that possibility in an appropriate

setting.
TABLE 2.1.1 Treatment approach to snakebite

PRE-HOSPITAL
First aid
Pressure bandage with immobilisation (PBI)
Transport
The patient is transported as soon as possible to a hospital that meets
all of the following criteria:
Doctor(s) able to manage snakebite
Laboratory capable of operating at all hours
Adequate antivenom stocking for definitive treatment
HOSPITAL
Resuscitation
Determine if the patient is envenomed
Assessment is performed serially over at least 12 hours and is based upon:
History
Physical examination
Laboratory investigations
Determine the type of antivenom required
Geographical area (prevalent indigenous snakes)
Clinical and laboratory features
CSL Snake Venom Detection Kit (SVDK)
Administer antivenom if indicated
Adjuvant and supportive treatment
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TABLE 2.1.2 Clinical effects of Australian Elapidae snakes
Venom-induced
consumptive
Category (genus) coagulopathy Neurotoxicity Myotoxicity Other effects
Brown (Pseudonaja) Always present with Rare Not present Early collapse (33%) or cardiac
significant arrest (5%)
envenoming Systemic symptoms frequently
absent* (50%)
Thrombotic microangiopathy (10%)
Tiger group Always present with Uncommon Uncommon Systemic symptoms common*
(Hoplocephalus, significant Slow onset over Slow onset over Thrombotic microangiopathy (<5%)
Notechis, envenoming hours hours
Tropidechis) May resolve
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spontaneously in
12–24 hours
Death adders Not present Common Not present Systemic symptoms common*
(Acanthophis) May have slow onset Local bite site pain often present
over hours
Continued
TOXICOLOGY HANDBOOK SPECIFIC CONSIDERATIONS

39
40
40
TABLE 2.1.2 Clinical effects of Australian Elapidae snakes—cont’d
Venom-induced
consumptive
Category (genus) coagulopathy Neurotoxicity Myotoxicity Other effects
Black (Pseudechis) Not present Not present Common Systemic symptoms common*
Mild anticoagulant May develop over Bite site pain and swelling of bitten
effect may occur hours to days limb usually significant
with raised APTT May be severe
and INR and result in
Fibrinogen remains renal failure
normal
Taipan (Oxyuranus) Always present with Common Rare Systemic symptoms common*
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significant May be rapid in Thrombotic microangiopathy (5%)
envenoming onset
Sea snakes Not present Uncommon Common Systemic symptoms common*

(Hydrophiidae) May be rapid in May develop over
onset minutes to
hours
*Non-specific systemic symptoms: nausea, vomiting, abdominal pain, sweating, diarrhoea.
There is no clinical risk stratification process that allows the clinician
to identify patients who can be discharged early or without laboratory
investigations. Patients with no obvious bite mark and no symptoms may
be envenomed. As a result, many patients each year who turn out not to
be envenomed are transferred to larger centres for definitive investigation
and observation.
It is unusual that a snake is identified with sufficient reliability to
preclude further observation or investigation.
PRE-HOSPITAL CARE
First aid
First aid aims to delay lymphatic spread of venom proximally from the
bite site and delay systemic effects until the patient is in a facility that
can administer adequate doses of antivenom if required.
• Keep the patient as calm and still as possible.

• Avoid unproven and harmful techniques such as tourniquets, ice,
cutting, sucking of the bite site or electric shocks.
41
• Apply a pressure bandage with immobilisation (PBI):
TOXICOLOGY HANDBOOK
— Broad (15 cm) elasticised pressure bandage over the entire limb
— Immobilisation of limb
— Immobilisation of the whole patient.
• If the bite is on the torso, apply local pressure over the site and
immobilise the patient.
• PBI may be left on for many hours while subsequent management
steps are completed. There are anecdotal reports of sudden
deterioration upon removal of the bandage up to 12 hours after
the bite.
• Do not wash the wound, as a wound swab may be required later for
the CSL Snake Venom Detection Kit (SVDK).
• The PBI is not removed until:
— The patient has been fully assessed in an appropriate hospital and
found to show no objective evidence of envenoming (normal
initial physical examination and laboratory investigations)
or
— Antivenom administration has commenced if found to be
envenomed.
Transport
All patients should be transported to a hospital that complies with all the
following criteria:
1 Doctor(s) present, able and willing to undertake snakebite
management, including definitive treatment of severe envenoming
and potential early complications (e.g. anaphylaxis)
ERRNVPHGLFRVRUJ
2 Laboratory facilities capable of performing necessary investigations
on a 24-hour basis
3 Antivenom stocks adequate for definitive treatment of severe
envenoming by all snakes indigenous to that geographical area, or
able to obtain antivenom within a clinically suitable timeframe.
If the initial receiving hospital does not comply with these criteria,
the stable patient is transferred or retrieved to a hospital that does.
If the patient is unstable, resuscitation commences and antivenom is
brought in by a retrieval service or any other means possible. During the
retrieval phase the patient should be observed for clinical evidence of
envenoming. If there is objective evidence of envenoming (e.g. definite
history of a bite with collapse/hypotension or clinical evidence of
abnormal bleeding or neurotoxicity), antivenom treatment may begin at
the peripheral site, or commence during transfer.
HOSPITAL MANAGEMENT
42
Resuscitation
•
42
Most patients present with a history of possible bite and do not

require immediate resuscitation.
TOXICOLOGY HANDBOOK
• Until early envenoming is excluded, patients should be assessed and

managed in an area equipped with cardiorespiratory monitoring and
resuscitation.
• Establish intravenous access.
• Rarely, management of immediate threats to airway, breathing and
circulation or control of seizures is required. Resuscitation proceeds
along conventional lines as outlined in Chapter 1.2.
• Potential early life-threats associated with Australian terrestrial snake
envenoming include:
— Cardiac arrest
— Sudden collapse (hypotension)
— Respiratory failure secondary to paralysis
— Seizures
— Uncontrolled haemorrhage secondary to severe venom-induced
consumptive coagulopathy (VICC).
Determine whether the patient is envenomed or not
The aim is to seek objective evidence of envenoming based on history,
physical examination and laboratory data (see Table 2.1.3). Serial physical
examinations (looking for bleeding or neurotoxicity) and investigations
(FBE, EUC, CK, INR aPTT, fibrinogen and D-dimer) are performed until
envenoming is diagnosed or at least 12 hours after the bite.
Point-of-care INR testing should never be used to diagnose
envenoming as very high false-positive and false-negative rates are
documented.
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TABLE 2.1.3 Assessment of snakebite
Laboratory
History Physical examination investigations
Geographical area of bite Vital signs Coagulation profile

Appearance of snake Mental status (INR and APTT
(usually only useful Evidence of bite (lack of required;
for death adders and evidence does not fibrinogen and
red-bellied black exclude envenoming) D-dimer
snakes) Lymphadenopathy desirable)
Anatomical site of bite Evidence of abnormal Full blood count
Number of strikes bleeding (especially Creatine kinase
Use of PBI bite site, gingival sulci) (CK)
Early symptoms (e.g. Evidence of descending Renal function and
collapse, nausea, symmetrical flaccid urinalysis
vomiting, bleeding, paralysis (ocular, small (blood/
weakness) muscles of face and myoglobin)
Pre-hospital course (e.g. bulbar function Consider also
hypotension, affected first) lactate 43
bleeding from IV Respiratory function (e.g. dehydrogenase
sites, urine output) PEFR) (LDH)
TOXICOLOGY HANDBOOK
Notes:
1 Point-of-care INR and D-dimer are inaccurate in VICC and should never be used.
2 The Commonwealth Serum Laboratories Snake Venom Detection Kit (SVDK) is not
used to determine whether a patient is envenomed (see section below).
Abnormalities on initial physical examination or laboratory studies

consistent with snake envenoming prompt immediate antivenom therapy
as outlined below.
If the patient remains clinically well and initial laboratory studies are
normal, the PBI is removed. If there is sudden clinical deterioration, it is
immediately reapplied, laboratory studies repeated and antivenom
administered.
If there is no discernible deterioration upon removal of the PBI, the
patient is observed and physical examination and laboratory studies
repeated at 1 hour following bandage removal and 6 and 12 hours
following the bite. If at any time clinical examination or laboratory
results suggest envenoming, appropriate antivenom is administered.
If there is no evidence of envenoming at 12 hours after the bite, the
patient is ready for discharge. However, patients should not be discharged
at night as subtle delayed neurotoxicity might not be detected.
Determine the type of monovalent antivenom required

Monovalent antivenom is recommended in preference to polyvalent
antivenom as it is more specific, cheaper and safer to administer.
Polyvalent antivenom contains the equivalent of one ampoule of each
monovalent antivenom. It contains a large protein load and is therefore
ERRNVPHGLFRVRUJ
associated with an increased risk of anaphylaxis. It is occasionally used
to treat black snake, death adder or taipan envenoming where the
specific monovalent antivenom is not readily available.
The choice of monovalent antivenom is based upon:
• Knowledge of snakes found in the area

•
Clinical presentation and laboratory abnormalities

• Snake identification may be useful in select cases. This should only
be performed by professional herpetologists.
In many regions, particularly in the south-west and south-east parts
of Australia, one vial each of brown snake and tiger snake monovalent
antivenom will cover the clinically important snakes based on the clinical
envenoming syndrome, particularly in the presence of VICC. Use of the
SVDK may be useful in regions where the range of possible snakes is
too broad to allow the use of one or two monovalent antivenoms.
44 Administer antivenom
• One vial of the relevant snake monovalent antivenom is required
44
to treat both children and adults for all snake types. It is given by
TOXICOLOGY HANDBOOK
intravenous infusion diluted in normal saline.

• The use of more than one vial or repeat does of antivenom is no
longer recommended based on in-vitro and clinical evidence from the
Australian Snakebite Project (ASP).
• Further details on specific monovalent antivenoms and their
administration are available in Chapter 6.
• Clinician(s) administering antivenom must be prepared to manage
anaphylaxis (see Appendix 6).
• Given the low prevalence of severe anaphylactic reactions to CSL
antivenoms (1% for monovalent; 5% for polyvalent), premedication
to prevent allergic reactions is not routinely indicated.
• Following the administration of antivenom, the patient’s clinical
status is monitored and laboratory investigations repeated after 6 and
12 hours and then every 12 hours until normalised.
• Even with adequate antivenom administration, it may take from 10
to 20 hours for coagulation studies to begin to improve in patients
with VICC and from 24 to 36 hours for them to return to normal.
Resolution of VICC is dependent on synthesis of new clotting factors
and administration of further doses of antivenom does not assist this
process.
Adjuvant therapy
General wound care and updating of tetanus prophylaxis may be required.
The benefit of clotting factor replacement in treating VICC is
controversial and the subject of ongoing research. It is reasonable to
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BOX 2.1.1 The CSL Snake Venom Detection Kit (SVDK)
The SVDK was designed to support the choice of a single monovalent
antivenom to use once a decision has been made to give antivenom.
The SVDK is not used to determine whether or not a patient is envenomed.
False positives and negatives occur; if the SVDK does not match the
clinical picture, treat the patient not the SVDK result.
If there is doubt about the snake responsible for the envenoming and the
SVDK is not helpful (e.g. possible early tiger or brown snake envenoming in
a geographical location where the two snakes coexist), two monovalent
antivenoms are superior to polyvalent antivenom.
The SVDK is ideally performed by a meticulous and experienced technician
according to the enclosed instructions.
The SDVK is performed using a bite-site swab, which can be accessed by
cutting a ‘key-hole’ in the PBI.
The SVDK may also be performed on urine (second-line).
The SVDK should never be performed on serum or blood.
45
administer fresh frozen plasma (FFP) following antivenom administration
TOXICOLOGY HANDBOOK
to patients who have active and potentially life-threatening bleeding.
Blood products hasten the recovery of INR in some patients but will
prolong coagulopathy in others especially when given early. Their
administration is not associated with earlier discharge from hospital.
The rare complications of snakebite such as neuromuscular paralysis,
myotoxicity or thrombotic microangiopathy with acute renal failure
require ongoing appropriate supportive care in a high-dependency or
intensive care unit in a tertiary hospital.
Serum sickness is unlikely after administration of one or two vials of
monovalent antivenom. Prednisolone 1 mg/kg/day (up to 50 mg/day) for
5 days may attenuate the severity of serum sickness should it develop.
References
Isbister GK, Brown SGA, McCoubrie DL, Green SL, Buckley NA. Snakebite in
Australia: a practical approach to diagnosis and treatment. Medical Journal of
Australia 2013; 199:763–768.
White J. A clinician’s guide to Australian venomous bites and stings: incorporating the
updated CSL antivenom handbook. Melbourne: CSL Ltd, 2012.
2.2 APPROACH TO MUSHROOM POISONING

Poisoning from ingestion of mushrooms occurs worldwide usually when
wild mushrooms containing toxins are misidentified as comestible species.
More than one individual may be poisoned simultaneously. The most
common presentation is a benign self-limited gastrointestinal disturbance
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but a number of other important toxic syndromes, including potentially
lethal hepatotoxicity, are recognised. Assessment and management is
based on the recognition of the principal clinical syndromes that may
develop following ingestion of toxic mushrooms. Patients may present
with mixed poisoning after ingestion of multiple mushroom species.
RISK ASSESSMENT
• The vast majority of mushroom poisoning cases in Australasia
manifest with acute gastrointestinal toxicity. A rapid resolution of
symptoms and good outcome with supportive care is anticipated.
• A variety of other toxic syndromes may develop and a favourable
outcome can usually be anticipated with good supportive care.
• Worldwide, cyclopeptide hepatotoxic poisoning, particularly from
Amanita phalloides, accounts for the majority of mushroom-related
deaths. This form of poisoning is reported but extremely rare within
Australasia.
46 — Within Australasia almost all cases of cyclopeptide hepatotoxic
poisoning have occurred in the Australian Capital Territory.
46
Amanita phalloides is thought to have been imported along with

TOXICOLOGY HANDBOOK
oak trees and is now naturalised particularly in the older suburbs

of Canberra. Amanita phalloides has also been reported in
Melbourne and Adelaide.
• Cyclopeptide hepatotoxic poisoning must be considered whenever
gastrointestinal symptoms develop more than 6 hours after ingestion
of mushrooms and with a high degree of suspicion if the mushrooms
were growing wild in Canberra.
• Children: accidental ingestion of wild mushrooms by children is

usually benign.
MUSHROOM SPECIES AND TOXINS
There are thousands of mushroom species and reliable mushroom
identification, even by expert mycologists, is difficult. In the clinical
setting, identification is frequently impossible because the mushrooms
are unavailable, decomposing, partly digested or cooked.
Numerous toxins are identified and are usually species-specific
(see Table 2.2.1).
Acute gastroenteritis is the most frequent manifestation of mushroom
poisoning. The causative toxins are not well-identified and probably
heterogeneous in nature. The cholinergic syndrome is secondary to
muscarine, a quaternary ammonium peripheral muscarinic agonist that
does not stimulate nicotinic receptors and does not cross the blood–brain
barrier. Glutaminergic toxicity is due to muscimol, which resembles
GABA and stimulates central GABA receptors, and ibotenic acid, which
resembles glutamic acid and stimulates central glutaminergic receptors.
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TABLE 2.2.1 Clinical syndromes of mushroom poisoning
Syndrome Clinical features Clinical course Toxin (mushroom species)

EARLY ONSET (WITHIN 6 HOURS)
Miscellaneous Malaise, abdominal pain, nausea, vomiting, Onset 30 min–3 hours Multiple mushroom genera
gastrointestinal* diarrhoea Resolution 6–24 hours but toxic mechanisms
not identified
Cholinergic* Vomiting, diarrhoea, lacrimation, salivation, Onset 30 min–2 hours Muscarine (Clitocybe and
urinary incontinence, bronchorrhoea, Inocybe species)
bronchospasm, miosis
Hallucinogenic* Ataxia, anxiety, mydriasis, tachycardia, Onset within minutes Psilocybin (Psilocybe
dyskinesias, delirium and hallucinations Resolution 4–6 hours species)
Disulfiram-like* Nausea, vomiting, tachycardia, facial flushing, Onset follows ethanol Coprine (Coprinus species)
sweating, chest pain consumption within
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up to 7 days of
mushroom ingestion
Glutaminergic* Dizziness, drowsiness, delirium, dysphoria, Onset 30 min–2 hours Ibotenic acid
hallucinations, myoclonus, hyperreflexia, Muscimol (Amanita
seizures muscaria and
pantherina)
Continued

47
48
48
TABLE 2.2.1 Clinical syndromes of mushroom poisoning—cont’d
Epileptogenic Nausea, vomiting, diarrhoea Gl symptoms within 4–6 Gyromitrin (Gyromitra

Headache, ataxia, fatigue, nystagmus, tremor, hours species)
vertigo, seizures (rare)
Delayed hepatotoxicity with raised Onset 2–3 days

transaminases (rare)
Delayed haemolysis and Onset 1–3 days after

methaemoglobinaemia (rare) hepatic injury
Immunohaemolytic Nausea, vomiting, epigastric pain and Onset 30 min–3 hours Paxillus species
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diarrhoea
Haemolytic anaemia, haemoglobinuria, In the following days

immune-complex nephritis and acute renal
failure
Pneumonic Nausea, vomiting and rhinitis Onset within 6 hours Inhalation of dried
Lycoperdonosis spores
Acute bronchopneumonia Within days
DELAYED ONSET (6–24 HOURS)
Hepatotoxic* Asymptomatic 6–18 hours Three classes of

cyclopeptide:
Nausea, vomiting, abdominal cramps and Onset 6–24 hours ● Amatoxins
diarrhoea ● Phallotoxins
● Virotoxins
Transient clinical improvement during 18–36 hours (Amanita, Galerina and
asymptomatic increase in hepatic Lepiota species)
transaminases
Progressive hepatic failure, kidney injury, 1–7 days

coagulopathy with progression to
multisystem organ failure and up to 30%
mortality
Recovery in survivors >7 days
Erythromelalgia Burning pain, redness and oedema of the Onset 24–72 hours Acromelic acids
hands and feet, exacerbated by heat and Resolution 8 days to
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relieved by cold 5 months
GREATLY DELAYED ONSET (>24 HOURS)
Nephrotoxic Anorexia, headache, nausea, vomiting, Onset 24–36 hours Orellanine (Cortinarius and
abdominal pain and flank pain A. smithiana species)
Interstitial nephritis and acute renal failure
Rhabdomyolysis Fatigue, myalgias, muscle weakness and Onset 24–72 hours (Tricholoma and Russula
myocarditis (very rare) species)
*Denotes syndromes described in Australia.

49
Gyromitrin is activated to monomethylhydrazine, which has a similar
mode of action to isoniazid and inhibits pyridoxine-dependent synthesis
of GABA. Psilocybin resembles lysergic acid diethylamide (LSD).
Coprine inhibits acetaldehyde dehydrogenase, a mode of action similar
to disulfiram. Amatoxins (chiefly α-amanitin) inactivate RNA
polymerase II and inhibit protein synthesis.
CLINICAL FEATURES
A variety of clinical syndromes may develop following ingestion of toxic
mushrooms. They are diagnosed on the basis of the clinical features and
the timing of the onset and duration of clinical features in relation to
mushroom ingestion (see Table 2.2.1). Laboratory abnormalities are
important in the diagnosis of some syndromes, especially hepatotoxicity.
Identification of the mushroom species by a mycologist is frequently
difficult or impossible but may provide important supportive evidence if
available.
50
Conventional food poisoning should be considered in the differential
50
diagnosis for any patient who presents with gastrointestinal symptoms

following ingestion of mushrooms.
TOXICOLOGY HANDBOOK
MANAGEMENT
Resuscitation
Patients may present with altered conscious state, seizures, cholinergic
crisis or significant hypovolaemia secondary to gastrointestinal fluid
losses. These priorities are managed along conventional lines as outlined
in Chapter 1.2: Resuscitation.
Supportive care
Patients may have significant gastrointestinal losses and require large
volumes of crystalloid solutions. Meticulous supportive care includes
laboratory monitoring of electrolytes as clinically indicated. Seizures,
delirium and hallucinations are managed along conventional lines as
outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation.
Decontamination
Administration of activated charcoal 50 g (1 g/kg in a child) is indicated
if onset of gastrointestinal symptoms is delayed beyond 6 hours after
ingestion.
Investigations
Examination of any available mushrooms by a mycologist is useful,
particularly in cases where ingestion of species containing cyclopeptide
hepatotoxins is considered.
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The Meixner test is a useful screening test in the asymptomatic
patient. Hydrochloric acid is added to a sample of the offending
mushroom placed on newspaper. A blue colour change suggests the
presence of cyclopeptide hepatotoxins, although false positives can occur.
Electrolytes and creatinine should be monitored where significant
gastrointestinal fluid losses occur. Liver function tests should be
monitored for 24–48 hours where ingestion of mushrooms containing
cyclopeptide hepatotoxins is suspected.
Methods of enhanced elimination are frequently considered in patients
with potential cyclopeptide hepatotoxic mushroom poisoning but
their effect on outcome has not been studied in controlled trials. If
cyclopeptide hepatotoxic mushroom poisoning is suspected, multiple-
dose activated charcoal (see Chapter 1.7: Enhanced elimination) may be
useful because amatoxin undergoes enterohepatic circulation.
51
Antidotes
Multiple antidotes and adjuvant therapies have been advocated in
TOXICOLOGY HANDBOOK
patients with potential cyclopeptide hepatotoxic mushroom poisoning but
their effect on outcomes has not been evaluated in controlled trials. They
include high-dose benzyl penicillin (penicillin G), cimetidine,
N-acetylcysteine and silibinin. If delayed onset of gastrointestinal
symptoms or rising hepatic transaminases raises suspicion of possible
cyclopeptide hepatotoxic mushroom poisoning, commence:
• N-acetylcysteine (see Chapter 4.17: N-acetylcysteine)

• Silibinin (if available) 5 mg/kg by intravenous infusion over 1 hour
followed by a continuous infusion of 20 mg/kg/day for up to 3 days
• Benzylpenicillin 600 mg/kg/day IV may be given if silibinin is not
available.
Atropine may be considered in patients with peripheral cholinergic
signs and symptoms (see Chapter 4.1: Atropine).
Management of seizures secondary to monomethylhydrazine
poisoning from ingestion of Gyromitra mushrooms is similar to the
management of isoniazid poisoning and includes administration of
pyridoxine (see Chapter 4.23: Pyridoxine).
Disposition and follow-up

• Asymptomatic paediatric patients may be observed at home
following suspected ingestion of wild mushrooms.
• Patients with early onset gastrointestinal illness are managed
supportively in a ward environment. They may be discharged when
clinically well. Patients with significant symptoms lasting more than
ERRNVPHGLFRVRUJ
6 hours should have liver function tests and renal function checked
prior to discharge. Abnormal liver or renal function prompts further
inpatient management.
• Patients with coma requiring intubation or significant CNS effects
require management in an intensive care setting.
• Cyclopeptide hepatotoxic mushroom poisoning is extremely rare and
most clinicians have very limited clinical experience. If this syndrome

is suspected due to delayed onset gastrointestinal symptoms or rising
hepatic transaminases, early consultation with a hepatologist and
clinical toxicologist is recommended. In severe cases, hepatic
transplantation has been attempted but prognosis remains poor.
References
Diaz JH. Syndromic diagnosis and management of confirmed mushroom poisonings.
Critical Care Medicine 2006; 33:427–436.
Enjalbert F, Rapior S, Nouguier-Soulé J et al. Treatment of amatoxin poisoning:
20-year retrospective analysis. Journal of Toxicology-Clinical Toxicology 2002;
52 40(6):715–757.
Persson H. Mushrooms. Medicine 2012; 40(3):135–138.
52
Roberts DM, Hall MJ, Falkland MM et al. Amanita phalloides poisoning and
treatment with silibinin in the Australian Capital Territory and New South Wales.
TOXICOLOGY HANDBOOK
Medical Journal of Australia 2013; 198:43–47.
2.3 APPROACH TO PLANT POISONING

Numerous pharmacologically-active substances are produced by plants
and many pharmaceutical agents and recreational drugs are of plant
origin. Serious human poisoning from plant exposures is, however,
extremely rare.
Exposure to toxic plants may occur unintentionally when they are
mistakenly identified as edible plants or when young children ingest
parts of plants, usually berries or seeds. Intentional exposure to toxic
plants occurs with recreational or medicinal intent or, less commonly, as
an attempt at deliberate self-harm. It often involves the ingestion of teas
made from the plant. Non-intentional cutaneous and ocular exposures
may also cause symptoms.
Assessment of plant exposures is difficult even when the plant is
positively identified because it is virtually impossible to quantify dose;
there is enormous variation in toxin concentrations between species,
plant part, location and season.
RISK ASSESSMENT
• Most plant exposures are asymptomatic or cause minor irritative
symptoms only.
• Plants containing calcium oxalate crystals may cause more severe
irritation to exposed mucous membranes.
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• A few plants or parts of plants are capable of causing severe
poisoning when ingested in sufficient quantity.
• Accurate plant identification usually allows refinement of the risk
assessment.
• In the absence of accurate plant identification, risk assessment relies
on knowledge of local plants and observation of clinical features and
progress.
• Children: significant plant poisoning is extremely rare. Ingestion of

yellow oleander or castor bean seeds can theoretically cause
significant poisoning but hospital assessment is not indicated unless
symptoms develop.
IMPORTANT PLANT TOXINS

Calcium oxalate
Some plants contain needle-like calcium oxalate crystals packaged into
bundles that can cause mechanical injury to mucosal membranes when 53
ingested. The plants most commonly associated with this type of injury
are Dieffenbachia spp. and Philodendron spp.
TOXICOLOGY HANDBOOK
Toxins capable of causing severe poisoning
A number of plant toxins are known to have caused significant human
poisoning or death following ingestion of fresh plant material. Important
examples are listed in Table 2.3.1 and discussed here.
Aconite (Aconitum spp. and Delphinium spp.) is found in some Asian
herbal medicines. It binds to voltage-dependent sodium channels leading
to permanent activation of cardiac muscle and voltage-dependent
nervous tissue receptors. Dose-dependent toxicity develops rapidly after
ingestion and manifests with CNS, cardiovascular and gastrointestinal
effects. Bradycardia and hypotension may progress to tachydysrhythmias
and cardiac arrest, paraesthesiae may progress to CNS depression,
respiratory depression, paralysis and seizures, and nausea and vomiting
may progress to diarrhoea and abdominal cramping.
Belladonna alkaloids (atropine, scopolamine, hyoscyamine) are found
in numerous plant species. Those most commonly associated with human
poisoning are belladonna (Atropa spp.), angel’s trumpet (Datura spp.) and
henbane (Hyoscyamus spp.). These alkaloids cause competitive blockade
of central and peripheral acetylcholine muscarinic receptors leading to the
anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome).
Cardiac glycosides of various types are found in all parts of several
plants, including foxglove (Digitalis purpurea), pink and white oleander
(Nerium spp.) and yellow oleander (Thevetia spp.). These all have
digoxin-like effects on cardiac conduction and Na+–K+ ATPase (see
Chapter 3.34: Digoxin: acute poisoning).
ERRNVPHGLFRVRUJ
TABLE 2.3.1 Plant toxins with potential to cause serious toxicity or
death following a single acute ingestion
Toxin(s) Plant(s) Clinical features
Aconite Aconitum spp. Severe cardiovascular,

Delphinium spp. neurological and
gastrointestinal toxicity
High mortality from ventricular
dysrhythmias and
cardiovascular collapse
Belladonna Datura spp. (jimsonweed, Anticholinergic poisoning:

alkaloids angel’s trumpet) tachycardia, delirium,
Atropa belladonna agitation, ileus, urinary
Hyoscyamus niger retention
(henbane)
Cardiac Digitalis spp. (foxglove) Bradycardia, dysrhythmias, GI

glycosides Nerium spp. (pink or disturbance,
54
white oleander) hyperkalaemia
54
Thevetia spp. (yellow

oleander)
TOXICOLOGY HANDBOOK
Colchicine Colchicum autumnale GI disturbance, bone marrow

(autumn crocus) depression, multi-system
Gloriosa superba (glory organ failure
lily)
Coniine Conium maculatum Bradycardia, tachycardia, GI

(poison hemlock) disturbance, ascending
paralysis, rhabdomyolysis,
renal failure
Cyanogenic Prunus spp. seed kernels Tachycardia, bradycardia,

glycosides (apricot, plum, pear, coma, acidosis, multi-
cherry, almond) system organ failure
Hypoglycin Blighia sapia (ackee) Hypoglycaemia, acidaemia,

vomiting, seizures
Nicotine Nicotiana spp. (tobacco) Tachycardia, hypotension,

tremor, sweating, GI
symptoms, seizures
Psychotropic Ipomea spp. (morning Acute psychosis, visual

alkaloids glory) seeds hallucinations
Lophophora williamsii
(peyote cactus)
Ricin Ricinus communis GI disturbance, multi-system

(castor beans) organ failure
Taxine Taxus spp. (yew) Bradycardia, dysrhythmias, GI

disturbance
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The antimitotic agent, colchicine, is found in all parts of the autumn
crocus (Colchicum autumnale) and glory lily (Gloriosa superba), and
human colchicine poisoning (see Chapter 3.31: Colchicine) is reported
after ingestion of bulbs and leaves.
Coniine is an alkaloid found in poison hemlock (Conium
maculatum). It is structurally related to nicotine and produces both
nicotinic effects and neuromuscular blockade with potential for death
by respiratory failure.
Amygdalin is a cyanogenic glycoside found in the seeds or pits of
apricots, almonds, apples, peaches and wild cherries (Prunus spp.).
Laetrile, derived from amygdalin from apricot pits, is sometimes
marketed as a health food. After ingestion, amygdalin is hydrolysed to
produce cyanide (see Chapter 3.33: Cyanide).
Hypoglycin A is found in the unripe fruit and seeds of the ackee tree
(Blighia sapida). It interferes with fatty acid metabolism and causes
hypoglycaemia. It also causes vomiting, CNS depression and seizures.
Nicotine is found in the tobacco plant (Nicotiana tabacum). 55
Excessive ingestion, inhalation or transdermal exposure leads to
overstimulation of nicotinic receptors. This manifests with GI symptoms,
TOXICOLOGY HANDBOOK
sweating, mydriasis, tachycardia, hypertension and seizures.
Psychotropic alkaloids include lysergic acid and mescaline. They act
as direct serotonin agonists and can produce vivid visual hallucinations.
Lysergic acid is found in morning glory seeds (Ipomea spp.) and
mescaline in the peyote cactus (Lophophora williamsii).
Ricin, a lectin, is found in the castor bean plant (Ricinus communis).
The highest concentration is in the seeds. An intracellular toxin, it
inhibits protein synthesis, leading to a severe gastrointestinal disturbance
together with cardiac, haematological, hepatic and renal toxicity.
Taxine is a mixture of alkaloids found in yew trees (Taxus spp.),
which inhibit both sodium and calcium currents. Ingestion of seeds
has produced gastrointestinal symptoms, paraesthesiae, mental status
changes, bradycardia, conduction blocks, ventricular dysrhythmias and
cardiac arrest.
CLINICAL FEATURES
The vast majority of plant exposures remain asymptomatic. Minor
transient gastrointestinal symptoms may be observed.
The clinical features of oxalate crystal ingestion are immediate onset
of pain and swelling usually affecting the lips, tongue, oral cavity and
pharynx. Rarely, severe exposures may produce dysphagia, profuse
salivation and upper airways obstruction. It may take days for symptoms
to subside.
Potentially serious exposures manifest onset of signs and symptoms
suggestive of the toxic mechanism. As detailed above, the clinical
ERRNVPHGLFRVRUJ
syndromes that may develop include cardiovascular collapse,
anticholinergic syndrome, nicotinic poisoning, cardiac glycoside
poisoning, colchicine or cyanide poisoning.
MANAGEMENT
Resuscitation
Immediate resuscitation is unlikely to be required except in the patient
with delayed presentation after severe poisoning. An important exception
is aconite poisoning in which death from ventricular dysrhythmias or
respiratory paralysis may occur within hours of ingestion. Resuscitation
follows standard ACLS protocols. Successful outcome from cardiac
arrest from aconite poisoning using cardiopulmonary bypass is reported.

The management of most plant poisonings entails supportive care and
56 monitoring along the standard lines described in Chapter 1.4: Supportive
care and monitoring. Particular attention to fluid and electrolyte status is
56
required with colchicine (see Chapter 3.31: Colchicine), aconite and ricin
TOXICOLOGY HANDBOOK
poisoning. Maintenance of euglycaemia with dextrose infusion is

required in ackee fruit poisoning. Management of seizures and delirium
requires administration of titrated doses of benzodiazepines as outlined
in Chapter 2.6: Seizures and Chapter 2.7: Delirium and agitation.
Investigations
Investigations are performed as dictated by clinical signs and symptoms.
Serum digoxin levels do not accurately reflect toxicity from cardiac
glycoside poisoning of plant origin.
Decontamination
Administration of oral activated charcoal 50 g (1 g/kg in a child) is
indicated where the risk assessment suggests the possibility of life-
threatening toxicity. Where there is any potential for imminent
depression in the level of consciousness or seizures, the airway must be
secured prior to administration of activated charcoal.
Skin exposure requires thorough washing of the exposed skin and
eye exposure requires thorough irrigation of the affected eye.
Antidotes
Physostigmine is useful in reversing severe anticholinergic poisoning
(see Chapter 4.21: Physostigmine). Cyanide antidotes may be useful
in treating cyanogenic glycoside poisoning (see Chapter 4.13:
Hydroxocobalamin and Chapter 4.26: Sodium thiosulfate). Digoxin
immune Fab in relatively high doses has been used successfully to
ERRNVPHGLFRVRUJ
reverse cardiotoxicity from oleander poisoning (see Chapter 4.6: Digoxin
immune Fab).
Not useful in plant poisoning.
Disposition
Hospital assessment or observation is not required if the patient is
asymptomatic or has minor gastrointestinal symptoms only and the plant
is identified as not having potential for serious toxicity. This is the case
for the vast majority of plant exposure cases.
Hospital assessment and observation is necessary if there has been
significant ingestion of plant material containing potentially life-
threatening toxins. Any patient with symptoms beyond minor
gastrointestinal ones should also be assessed in hospital. The period of
observation continues until all risk of serious toxicity has elapsed. Where
significant toxicity develops, the level of care and length of stay will be 57
determined by the clinical course.
Dermal, mucosal and ophthalmic plant exposures
TOXICOLOGY HANDBOOK
A wide variety of plants are able to cause either primary or allergic
contact dermatitis. Some plants such as nettles have a specialist stinging
apparatus that acts like a hypodermic syringe to deliver irritant chemical
to the skin. Contact dermatitis is frequently associated with exposure to
the sap of certain plants such as the mango tree. It is rarely serious.
Allergic contact dermatitis results from type IV hypersensitivity response
to plant exposures. Certain plants have a greater propensity to cause
allergic contact dermatitis.
References
Challoner KR, McCarron MM. Castor bean intoxication. Annals of Emergency
Medicine 1990; 19:1177–1183.
Chan TY. Aconite poisoning. Clinical Toxicology 2009; 47(4):279–285.
Eddleston M, Ariaratnam CA, Sjostrom L et al. Acute yellow oleander (Thevetia
peruviana) poisoning: cardiac arrhythmias, electrolyte disturbances, and serum
cardiac glycoside concentrations on presentation to hospital. Heart 2000;
83:301–306.
Eddleston M, Rajapakse S, Rajakanthan K et al. Anti-digoxin Fab fragments in
cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled
trial. Lancet 2000; 355:967–972.
Froberg B, Ibrahim D, Furbee RB. Plant poisoning. Emergency Clinics of North
America 2007; 25:375–433.
Rajapakse S. Management of yellow oleander poisoning. Clinical Toxicology 2009;
47(3):206–212.
Schep LJ, Slaughter RJ, Beasley DM. Nicotinic plant poisoning. Clinical Toxicology
2009; 47(8):771–781.
Suchard JR, Wallace KL, Gerkin RD. Acute cyanide toxicity caused by apricot kernel
ingestion. Annals of Emergency Medicine 1998; 32:742–744.
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2.4 COMA
Coma describes an altered mental status where the patient cannot be
roused. It is a common manifestation of acute poisoning by many agents
(see Table 2.4.1).
In a potentially poisoned patient, coma may be the result of:
• Direct toxic effect on the CNS – wakefulness and consciousness

depend on complex mechanisms involving many pathways and
neurotransmitter systems
• Secondary effect of poisoning on the CNS – hypoxaemia,
hypoglycaemia, hyponatraemia, hypotension, seizures or cerebral
oedema
• Alternative non-toxicological diagnoses – metabolic encephalopathy,
neurotrauma, space-occupying lesion or meningoencephalitis.
58 Coma presents an immediate threat to life, irrespective of the
underlying cause. Assessment and management is a core emergency
58
competency. With a few important exceptions, most agents that cause

TOXICOLOGY HANDBOOK
toxic coma produce a relatively benign and temporary alteration in

mental status that has a good prognosis with thorough supportive care.
MANAGEMENT
Resuscitation
Establishment of airway and ventilation is the immediate priority
irrespective of the aetiology of coma. This is initially achieved using
positioning techniques, oropharyngeal airway and bag and mask
ventilation with 100% oxygen. Definitive control is then achieved as soon
as practical with emergency rapid sequence endotracheal intubation. The
only exceptions to this process are when hypoglycaemia is detected or
there is clinical suspicion of opioid intoxication. In these circumstances,
bag and mask ventilation may continue while awaiting a response to
administration of concentrated dextrose solution or naloxone. If coma does
not rapidly resolve, proceed with rapid sequence endotracheal intubation.
Poisoning is a dynamic illness. The patient’s ability to maintain an
airway and ventilate effectively may change in a short period of time.
Ideally, this is anticipated and prepared for on the basis of an early risk
assessment. For example, the patient who presents shortly after ingesting
>30 mg/kg of a tricyclic antidepressant is expected to have a rapid
decline in level of consciousness within 2 hours.
A common pitfall in acute poisoning management is to assume that
coma is likely to be short-lived and to leave the airway unprotected for a
prolonged period of time. This increases the risk of pulmonary aspiration,
hypoxaemia and hypoventilation. Unlike trauma, where convention
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TABLE 2.4.1 Toxicological causes of coma
PRIMARY NEUROLOGICAL EFFECT
Alcohols Cholinergic agents

Ethanol Carbamates
Ethylene glycol Dementia acetylcholinesterase
Isopropyl alcohol inhibitors (e.g. donepezil)
Methanol Nicotine
Antipsychotic agents Organophosphates
Amisulpride Hydrocarbons
Chlorpromazine Essential oils
Clozapine Toluene
Olanzapine Local anaesthetics
Quetiapine Bupivacaine
Anticonvulsant agents Cocaine
Carbamazepine Lignocaine
Lamotrigine Ropivacaine
Valproic acid Mushrooms
Antidepressants Gyromitra species 59
Selective serotonin reuptake Non-steroidal anti-inflammatory
inhibitors agents
Tricyclic antidepressants Ibuprofen
TOXICOLOGY HANDBOOK
Antihistamines Mefenamic acid
Diphenhydramine Opioids
Promethazine Codeine
Antimalarial agents Heroin
Chloroquine Morphine
Hydroxychloroquine Methadone
Quinine Sedative-hypnotic agents
Baclofen Barbiturates
Beta-adrenergic blockers Benzodiazepines
Propranolol Chloral hydrate
Centrally acting alpha-2-agonists Gamma-hydroxybutyrate
Clonidine Non-benzodiazepine agents
Oxymetazoline (zolpidem, zopiclone)
SECONDARY EFFECT
Cerebral oedema Neuroleptic malignant syndrome

Salicylates Antipsychotic agents
Valproic acid Seizures
Hypoglycaemia Bupropion
Insulin Isoniazid
Sulfonylureas Tramadol
Hypotension Venlafaxine
Calcium channel blockers Serotonin syndrome
Cardiac glycosides (e.g. digoxin) Monoamine oxidase inhibitors
Hypoxaemia (systemic or cellular) Selective noradrenaline reuptake
Agents causing inhibitors (e.g. venlafaxine)
methaemoglobinaemia Selective serotonin reuptake
Carbon monoxide inhibitors
Cyanide
Hydrogen sulfide
ERRNVPHGLFRVRUJ
dictates intubation at a Glasgow Coma Scale score (GCS) of 8, there is
no definite measure of conscious state in poisoning that predicts the
need for intubation. A patient’s ability to guard their airway is poorly
correlated to GCS. The probability of aspiration is increased with any
GCS less than 15, especially where there is delay to presentation.
Once neuromuscular paralysis and intubation is achieved, it is vital to
ventilate the patient at an appropriate minute volume. Several poisonings

are associated with metabolic acidosis and compensatory
hyperventilation to achieve respiratory alkalosis (e.g. salicylate,
methanol, ethylene glycol). If hyperventilation is not maintained
following paralysis and mechanical ventilation, acute respiratory acidosis
results in rapid clinical deterioration and possibly death.
Risk assessment
Coma is usually a predictable response to poisoning where the agent and
60 dose are known. Where the original risk assessment did not predict
coma, it must be reassessed. It usually means that there has been
60
ingestion of a different or additional agents, a larger dose has been

ingested or that the patient has a non-toxicological cause for coma.
TOXICOLOGY HANDBOOK
Where the patient presents with coma of unknown origin and there is
no definite history of ingestion, the clinician must rigorously evaluate the
historical, clinical and laboratory features of the case in order to:
• Diagnose alternative non-toxicological causes of coma

• Diagnose important complications of coma
• Diagnose specific toxicities where specific interventions (enhanced
elimination techniques or antidotes) are necessary to ensure a good
outcome.
Toxic agents usually act on the CNS in a global and symmetrical
fashion and any focal or unilateral neurological sign is highly suggestive
of an alternative cause.
Patients may present having had significant impairment in level of
consciousness in the pre-hospital phase for varying periods of time.
These patients are at risk of a number of secondary complications, which
may have greater impact on morbidity and mortality than the intoxication
itself. These complications must be specifically sought and managed in
any patient presenting with coma. They include:
• Rhabdomyolysis
• Acute renal failure
• Compartment syndromes
• Pressure areas
• Hypoxic brain injury.
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Supportive care, monitoring and disposition
All patients requiring intubation and ventilation are admitted to an
intensive care unit for ongoing supportive care. The following are
important to minimise the complications of coma in the admitted patient:
• Monitoring of conscious state and airway
• Respiratory toilet and prophylaxis (mobilisation and/or
physiotherapy)
• Fluid monitoring and management
• Bladder care (indwelling catheter)
• Prevention of pressure areas
• Thromboembolism prophylaxis
• Mobilisation as mental status changes resolve.
Investigations
• Screening (12-lead ECG, BGL and serum paracetamol level)
— These tests are particularly important in the comatose patient 61
where no ingestion history is available
— A measurable paracetamol level may mandate empiric NAC if
TOXICOLOGY HANDBOOK
dose or time of ingestion cannot be determined
• To detect toxic ingestions for which specific interventions are
required
— Arterial blood gases, anion gap and lactate
— Osmolality and osmolar gap
— Specific drug levels: carbamazepine, ethanol, ethylene glycol (when
available), methanol (when available), salicylate, valproic acid
• To detect and assess complications
— Urea and electrolytes
— Liver function tests
— CK
— Chest X-ray
• To exclude or confirm important differential diagnoses
— Urea and electrolytes
— Liver function tests
— Cranial CT scan
— Lumbar puncture
— Blood and urine cultures
— EEG
Enhanced elimination techniques and antidote administration

The vast majority of patients presenting with or developing toxic coma
are assured of a good outcome with timely institution of supportive care.
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TABLE 2.4.2 Agents causing coma that may require
specific intervention
Carbamazepine Salicylate (severe poisoning only)

Multi-dose activated charcoal Haemodialysis
Haemodialysis Sulfonylureas
Isoniazid Dextrose
Pyridoxine Octreotide
Opioids Toxic alcohols (ethylene glycol,
Naloxone methanol)
Organophosphates Ethanol/fomepizole
Atropine Haemodialysis
Pralidoxime Valproic acid
Phenobarbitone Haemodialysis
Multi-dose activated charcoal
Haemodialysis
62 There are a small number of specific agents where specific interventions

are indicated (see Table 2.4.2). Details of management of these agents
62
are found in the relevant toxin and antidote sections in Chapter 3 and
TOXICOLOGY HANDBOOK
Chapter 4. Poisoning with carbamazepine, valproic acid or

phenobarbitone should be excluded with specific drug levels in any
comatose patient with access to these anticonvulsant agents. Toxic
alcohol and salicylate poisoning must be excluded in any comatose
patient with metabolic acidosis.
References
Daly FFS, Little M, Murray L. A risk assessment approach to the management of
acute poisoning. Emergency Medicine Journal 2006; 23:396–399.
International Liaison Committee on Resuscitation. 2005 American Heart Association
Guidelines for Cardiopulmonary and Emergency Cardiovascular Care – Part 10.2:
Toxicology in ECC. Circulation 2005; 112(24 Supplement I):IV126–IV132.
Isbister GK, Downes F, Sibbritt D et al. Aspiration pneumonitis in an overdose
population: frequency, predictors and outcomes. Critical Care Medicine 2004;
32:88–93.
2.5 HYPOTENSION
Hypotension is assessed and managed during the resuscitation phase of
poisoning management. If detected later in the clinical course, the
clinician returns to the resuscitation phase and specifically addresses
priorities in the usual order (initially airway, breathing and circulation).
Hypotension is common in poisoned patients. It is usually mild,
secondary to peripheral vasodilation and responsive to basic fluid
resuscitation. However, poisoning secondary to cardiotropic medications
is frequently associated with refractory hypotension of multifactorial
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origin and mortality is much higher. Similarly, hypotension that is
refractory to basic fluid resuscitation heralds a much worse outcome
unless perfusion is rapidly restored.
In a hypotensive patient, following attention to airway and breathing,
a series of interventions may be followed until a satisfactory response is
achieved:
1 Check cardiac rhythm and review a current 12-lead ECG.
Commence continuous ECG monitoring until patient is stabilised
and risk assessment is reviewed.
2 Ensure adequate intravenous access.
3 Correct cardiac dysrhythmias. Under certain circumstances,
standard resuscitation guidelines need to be disregarded and
the administration of specific antidotes may be a priority (see
Chapter 1.2: Resuscitation).
4 Give 10–20 mL/kg of IV crystalloid to ensure euvolaemia. Further
fluid challenge may be indicated but depends on the individual risk 63
assessment. For example, in iron or colchicine intoxication, fluid
losses may be large and fluid requirements ongoing. In contrast, in
calcium channel blocker intoxication excessive fluid resuscitation
TOXICOLOGY HANDBOOK
may lead to pulmonary oedema.
5 Consider specific antidotes:
• Digoxin-specific antibodies (digoxin)
6
• Calcium (calcium channel blockers).
Consider atropine and electrical pacing. Unfortunately, these
interventions rarely provide a definitive solution in the poisoned
patient.
7 Commence inotropic agents. The agent of choice depends on
the intoxication and the results of invasive haemodynamic
monitoring. It is usually wise to commence with the agent most
available and with which the attending staff are most familiar.
Choices include:
• Noradrenaline (norepinephrine)
• Adrenaline (epinephrine)
8
• Dobutamine.
Commence central haemodynamic monitoring.
9 Consider high-dose insulin therapy (see Chapter 4.14: Insulin (high
dose)).
10 Consider extraordinary manoeuvres such as extracorporeal
membrane oxygenation (ECMO).
Reference
Vanden Hoek TL, Morrison LJ, Shuster M et al. Part 12: Cardiac arrest in special
situations: 2010 American Heart Association guidelines for cardiopulmonary and
emergency cardiovascular care. Circulation 2010; 122:S829–S861.
ERRNVPHGLFRVRUJ
2.6 SEIZURES
Toxic seizures are usually generalised and self-limiting and easily
controlled with intravenous benzodiazepines. The most common causes
of toxic seizures in Australasia are venlafaxine, bupropion, tramadol and
amphetamines (see Table 2.6.1 for a summary of causes). Toxic seizures

are frequently of delayed onset as a result of extended-release
formulations of several of these agents.
Seizures are also a prominent manifestation of a number of
withdrawal syndromes, in particular those associated with ethanol and
benzodiazepines.
In certain poisonings, seizures herald severe intoxication and a grave
prognosis unless definitive care is rapidly instituted (e.g. chloroquine,
propranolol, salicylates, theophylline, tricyclic antidepressants).
Seizures of any cause are treated as a matter of priority. Prolonged
64 seizure activity is associated with irreversible CNS injury. Secondary
64
TOXICOLOGY HANDBOOK
TABLE 2.6.1 Toxicological causes of seizures
Anticonvulsants Local anaesthetic agents

Carbamazepine Lignocaine
Topiramate Nicotine
Antidepressants Non-steroidal anti-inflammatory
Bupropion agents
Citalopram Mefenamic acid
Desvenlafaxine Opioids
Escitalopram Dextropropoxyphene
Tricyclics Pethidine
Venlafaxine Propranolol
Antidysrhythmic agents Tramadol
Quinidine Salicylates
Antihistamines Sympathomimetic agents
Antimalarial agents Amphetamine and its derivatives
Chloroquine Cocaine
Hydroxychloroquine Synthetic cannabinoids and
Quinine cathinones
Antipsychotic agents Theophylline
Atypical antipsychotics Withdrawal syndromes
Butyrophenones Alcohol
Olanzapine Barbiturates
Phenothiazines Benzodiazepines
Quetiapine Non-benzodiazepine sedative-
Baclofen hypnotic agents (e.g.
Isoniazid gamma-hydroxybutyrate,
Hypoglycaemic agents zopiclone, zolpidem)
Insulin
Sulfonylureas
ERRNVPHGLFRVRUJ
hypoxia and acidosis increase the susceptibility for dysrhythmias.
Secondary hyperpyrexia and rhabdomyolysis may lead to dehydration,
hyperkalaemia and renal failure.
Phenytoin is not indicated in the management of toxic seizures.
The presence of focal or partial seizures indicates a focal
neurological disorder that is either a complication of poisoning or
non-toxicological in origin. In either case, prompt further investigation is
warranted.
MANAGEMENT
See Chapter 1.2: Resuscitation.
1 Attention to airway, breathing and circulation. If coma preceded onset
of seizures (e.g. tricyclic antidepressant poisoning), proceed to rapid
sequence intubation and ventilation as the steps below are taken.
2 Administer oxygen.
3 Check cardiac rhythm and output. 65
4 Establish intravenous access.
5 Check bedside blood glucose level and correct hypoglycaemia if
present.
TOXICOLOGY HANDBOOK
6 Give an intravenous benzodiazepine (e.g. diazepam 5–10 mg;
children 0.1–0.3 mg/kg/dose over 3–5 minutes). Repeat if necessary.
7 Consider barbiturates as second-line therapy for refractory seizures in
acute poisoning (e.g. phenobarbitone 100–300 mg slow IV; children
10–20 mg/kg slow IV; or thiopentone 3–5 mg/kg if ventilated).
8 Pyridoxine is a third-line agent that may be indicated in intractable
seizures secondary to isoniazid and other hydrazines (gram for gram
dose to match suspected isoniazid dose, or 5 g IV; children 70 mg/kg
not exceeding 5 g).
References
Kunisaki TA, Augenstein WL. Drug- and toxin-induced seizures. Emergency Medical
Clinics of North America 1994; 12(4):1027–1056.
Shah ASV, Eddleston M. Should phenytoin or barbiturates be used as second-line
anticonvulsant therapy for toxicological seizures? Clinical Toxicology 2010;
48:800–805.
2.7 DELIRIUM AND AGITATION

See also Chapter 2.9: Anticholinergic syndrome.
Delirium is characterised by an altered conscious state with impaired
cognition. The key diagnostic features are shown in Table 2.7.1.
Intoxication with a variety of agents may present with agitation and
delirium (Table 2.7.2). The alteration in CNS function is usually a
transient direct toxic effect that resolves along with other features of
ERRNVPHGLFRVRUJ
TABLE 2.7.1 Diagnostic features of delirium (based on DSM-V criteria)
1 Disturbance in attention (reduced ability to direct, focus, sustain and

shift attention) and awareness
2 Change in cognition (memory deficit, disorientation, language
disturbance, perceptual disturbance) that is not better accounted for by
a pre-existing, established or evolving dementia

3 The disturbance develops over a short period (usually hours to days)
and tends to fluctuate during the course of the day
4 There is evidence from the history, physical examination or laboratory
findings that the disturbance is caused by a direct physiological
consequence of a general medical condition, an intoxicating substance,
medication use or more than one cause
intoxication. Secondary complications or concomitant medical

emergencies may contribute to altered CNS function and these are listed
in Tables 2.7.3 and 2.7.4.
66
DUTY OF CARE
66
The patient with delirium has an altered mental state with cognitive
TOXICOLOGY HANDBOOK
impairment and is not competent to make decisions about their own

welfare. The clinician has a duty of care to the patient to protect them
from serious harm or death. The clinician also has a duty of care to other
patients, staff, visitors and the community at large to protect them from
being harmed by the actions of the delirious patient. Failure to control
the situation (allowing the patient to abscond or injure themselves)
represents an act of omission. While the delirium persists, temporary
physical restraint and pharmacological sedation, perhaps against the
patient’s wishes at the time, is appropriate.
MANAGEMENT
Resuscitation
Airway, breathing and circulation are managed as appropriate.
Atypical seizures or non-convulsive status epilepticus should be
considered and treated with benzodiazepines.
Check bedside serum glucose as soon as possible in all patients with
altered mental status to exclude hypoglycaemia. If the serum glucose is
<4.0 mmol/L, 50 mL of 50% glucose (5 mL/kg 10% glucose in children)
is given intravenously. The result may be confirmed later with a formal
serum glucose measurement. If hypoglycaemia is detected, the
underlying cause must be considered and managed.
A temperature >38.5°C is an indication for continuous core-
temperature monitoring. A temperature >39.5°C is an emergency that
requires prompt management to prevent multiple organ failure and
neurological injury.
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TABLE 2.7.2 Toxicological causes of agitation and delirium
Alcohol
Anticholinergic syndrome
Antidepressants
Bupropion
Monoamine oxidase inhibitors
Venlafaxine
Atypical antipsychotic agents
Clozapine
Olanzapine
Quetiapine
Baclofen
Benzodiazepines and other sedative-hypnotic agents (e.g. zolpidem)
Cannabis
Hallucinogenic agents
Dimethyltryptamine (DMT)
Ketamine
Phencyclidine
2,5-Dimethoxy-4-iodophenethylamine (2C-I) 67
Neuroleptic malignant syndrome (NMS)
Nicotine
Salicylates
TOXICOLOGY HANDBOOK
Serotonin syndrome
Sympathomimetic syndrome
Amphetamine and its derivatives
Cocaine
Synthetic cannabinoids
Synthetic cathinones
Theophylline
Withdrawal syndromes
TABLE 2.7.3 Complications of agitation in the poisoned patient
Aspiration pneumonitis
Deep vein thrombosis and pulmonary embolism
Fluid, electrolyte and acid–base disturbances, most commonly dehydration
Hypoventilation, hypoxia
Hyperthermia
Physical injury to the patient or others
Rhabdomyolysis
Risk assessment
Delirium is usually a predictable response to poisoning where the agent
and dose are known. If the original risk assessment did not predict
delirium, it must be reassessed. It usually indicates that there has been
ingestion of different or additional agents, or that the patient has a
non-toxicological cause for delirium.
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TABLE 2.7.4 Other conditions mimicking or contributing to agitation
Acid–base disturbance
Behavioural disturbance
CNS infection (e.g. encephalitis)
Dementia
Electrolyte disturbance (e.g. hyponatraemia)

Endocrine emergency (e.g. thyroid storm)
Head injury
Hypoglycaemia
Hypoxia
Organ failure (e.g. hepatic encephalopathy)
Psychosis
Seizures (e.g. non-convulsive status)
Stroke
Trauma (e.g. subdural haemorrhage)
Withdrawal (e.g. alcohol or sedative-hypnotic agents)
TABLE 2.7.5 Agents or syndromes associated with delirium and

68
agitation that may require specific interventions
68
Agent Possible interventions

TOXICOLOGY HANDBOOK
Anticholinergic Physostigmine (see Chapter 4.21: Physostigmine)

agents
Neuroleptic Bromocriptine
malignant
syndrome
Salicylates Urinary alkalinisation

Haemodialysis
Serotonin syndrome Cyproheptadine (see Chapter 4.3: Cyproheptadine)

Neuromuscular paralysis, intubation and ventilation
Theophylline Multi-dose activated charcoal

Haemodialysis
Where the patient presents with delirium but no definite history of

ingestion, the clinician must rigorously evaluate the historical, clinical
and laboratory features of the case in order to diagnose:
• Important complications of delirium (see Table 2.7.3)

• Alternative (non-toxicological) causes (see Table 2.7.4)
• Toxicities or syndromes where specific interventions (enhanced
elimination techniques or antidotes) are necessary to ensure a good
outcome (see Table 2.7.5).

The patient is managed in a calm environment to minimise external
stimulation and crowding. Repeated reassurance and explanation are
ERRNVPHGLFRVRUJ
important. One-on-one nursing is usually necessary to allow close
observation and management during the initial stages. If the patient
remains extremely agitated with an immediate risk of harming themselves
or others, temporary physical restraint is required until pharmacological
sedation can be achieved. The medical team’s duty of care to the patient
should be explained. Physical restraint is achieved quickly by broad-
based control of the arms and legs. It must never threaten the airway or
breathing and is only used as a temporary measure until appropriate
pharmacological sedation is instituted.
For sedation, intravenous benzodiazepines titrated to effect are
first-line agents. It is best to use an agent with a duration of effect likely
to match the anticipated duration of delirium, usually diazepam. In mild
cases, oral dosing may be appropriate. In more severe cases, or in any
case with physical restraint, intravenous dosing will be required.
Repeated doses of intravenous diazepam 5 mg should be given every
2–5 minutes until gentle sedation is achieved.
Antipsychotic agents such as haloperidol or droperidol are second- 69
line agents. They are highly effective but associated with acute
extrapyramidal (akathisia and dystonia) and anticholinergic effects. They
TOXICOLOGY HANDBOOK
should be avoided if anticholinergic syndrome is suspected. Droperidol
has been associated with QT prolongation, cardiac dysrhythmias and
sudden death in a very small number of cases. Recent reviews suggest
this is extremely rare, but it should be avoided if QT prolongation or
significant electrolyte disturbance is suspected.
Atypical antipsychotic agents (e.g. olanzapine) are rapidly acting and
frequently have a calming effect without major sedation in patients with
prominent psychotic symptoms. They may be given sublingually, orally
or intramuscularly. They are associated with fewer extrapyramidal effects
than haloperidol or droperidol.
Once agitation is adequately controlled, the patient is admitted to an
area capable of providing a sufficient level of ongoing close supervision
and monitoring, and where further intravenous sedation can be
administered if required. This is usually an emergency observation or
high-dependency unit. Delirium may persist for days, depending on the
cause. Patients with anticholinergic delirium frequently develop urinary
retention and attempts to achieve adequate sedation are doomed to failure
until this is relieved by placement of an indwelling urinary catheter.
General supportive care as detailed in Chapter 1.4: Supportive care
and monitoring includes:
• Monitoring of conscious state and airway

• Respiratory toilet and prophylaxis (mobilisation and/or chest
physiotherapy)
• Fluid monitoring and management
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• Bladder care (indwelling urinary catheter)
• Prevention of pressure areas
• Thromboembolism prophylaxis
• Mobilisation as mental status changes resolve.
Investigations
Investigations in acute poisoning are used either as screening tests or for

specific purposes. Specific investigations in the patient with agitation or
delirium should be ordered selectively where it is anticipated that the
results will refine risk assessment, exclude significant complications or
exclude potential non-toxicological diagnoses.
Enhanced elimination techniques and antidote administration
There are relatively few instances where these interventions are required
in the management of agitation or delirium (see Table 2.7.5). For the use
of physostigmine in anticholinergic delirium see Chapter 2.9:
70 Anticholinergic syndrome and Chapter 4.21: Physostigmine.
70
References
Carter LC, Dawson AH. Acute delirium. In: Dart RC, ed. Medical Toxicology. 3rd
TOXICOLOGY HANDBOOK
edn. Philadelphia: Lippincott Williams & Wilkins; 2004: Ch 15.

Chan EW, Taylor DM, Knott JC. Intravenous droperidol or olanzapine as an adjunct to
midazolam for the acutely agitated patient; a multicenter, randomized, double-blind,
placebo-controlled clinical trial. Annals of Emergency Medicine 2013; 61:72–81.
Horowitz BZ, Bizovi K, Moreno R. Droperidol – behind the black box warning.
Academic Emergency Medicine 2002; 9(6):615–618.
Isbister GK, Calver LA, Page CB et al. Randomised controlled trial of intramuscular
droperidol versus midazolam for violence and acute behavioral disturbance: the
DORM study. Annals of Emergency Medicine 2010; 56:392–401.
2.8 SEROTONIN SYNDROME

Serotonin syndrome is the clinical manifestation of excessive stimulation
of serotonin receptors in the CNS. This occurs when excess serotonin
(5-hydroxytryptamine) accumulates in the CNS, secondary to a number
of pharmacological mechanisms: inhibition of serotonin metabolism
(monoamine oxidase inhibitors), prevention of serotonin reuptake in
nerve terminals (serotonin reuptake inhibitors), serotonin release or
increased intake of serotonin precursors (tryptophan).
CLINICAL FEATURES
Serotonin syndrome manifests as a wide variety of signs and symptoms
that reflect the triad of clinical features: mental status changes,
autonomic stimulation and neuromuscular excitation (see Table 2.8.1).
There is a continuous clinical spectrum of severity ranging from very
mild symptoms in ambulatory patients to a fulminant life-threatening
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TABLE 2.8.1 Clinical features of serotonin syndrome
Autonomic
Mental status changes stimulation Neuromuscular excitation
Apprehension Diarrhoea* Clonus (esp. ocular and

Anxiety Flushing ankle)*
Agitation, psychomotor Hypertension Hyperreflexia*
acceleration and Hyperthermia† Increased tone (lower limbs
delirium* Mydriasis* > upper limbs)*
Confusion Sweating* Myoclonus*
Tachycardia* Rigidity
Tremor
*Clinical features significantly associated with diagnosis (Hunter Serotonin Toxicity
Criteria).
†
Hyperthermia >38°C is not significantly associated with the diagnosis but is present
in severe cases.
syndrome characterised by generalised rigidity, autonomic instability,

marked mental status changes and hyperthermia. Without prompt 71
intervention, this severe syndrome progresses to rhabdomyolysis, renal
failure, disseminated intravascular coagulation (DIC) and death.
TOXICOLOGY HANDBOOK
Symptoms are usually of rapid onset and may be evident within hours
of changes in medication or overdose. Similarly, the syndrome resolves
over hours (up to 24–48 in severe forms) following discontinuation of
the causative agent and the institution of supportive care. Serotonin
syndrome after deliberate self-poisoning usually develops within the first
8 hours and frequently after the patient presents to hospital.
DIAGNOSIS
Serotonin syndrome is a clinical diagnosis and requires the history of
ingestion of one or more serotonergically-active agents (or a change in
their dose), the presence of characteristic clinical features and a high
index of suspicion. Some symptoms are more significantly associated
with the diagnosis (see Table 2.8.1) and diagnostic algorithms have been
developed (see Figure 2.8.1)
Clinical settings in which serotonin syndrome may develop include:
• Introduction or increase in dose of a single serotonergic drug

• Change in therapy from one serotonergic drug to another without an
adequate intervening ‘washout’ period
• Drug interaction between two serotonergic agents
• Interaction between serotonergic drug and an illicit drug or herbal
preparation
• Deliberate self-poisoning with serotonergic agent(s).
Numerous agents are implicated in the development of serotonin
syndrome, of which the most important ones are listed in Table 2.8.2.
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FIGURE 2.8.1 Algorithm for diagnosis of serotonin syndrome
Serotonergic agent
ingestion or overdose
S
Spontaneous clonus yes E
R
Agitation O
no OR T
Diaphoresis O
OR N
I
Inducible clonus OR Hypertonia AND N
yes yes
Ocular clonus Pyrexia (>38oC)
T
O
no no X
I
C
I
72 Tremor yes Hyperreflexia yes T
Y
72
no no
TOXICOLOGY HANDBOOK
NOT clinically significant serotonin toxicity
Source: Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to
diagnosis and treatment. Medical Journal of Australia 2007; 187(6):361–365.
TABLE 2.8.2 Agents implicated in development of serotonin syndrome
Analgesics and antitussives Selective serotonin

Dextromethorphan reuptake inhibitors
Fentanyl (SSRIs)
Pethidine Citalopram
Tramadol Escitalopram
Antidepressants Fluoxetine
Tricyclic antidepressants Fluvoxamine
Illicit drugs Paroxetine
Amphetamines Sertraline
Methylenedioxymethamphetamine Serotonin and
(MDMA; ecstasy) noradrenaline reuptake
Herbal preparations inhibitors (SNRIs)
Spirulina Bupropion
St John’s wort (Hypericum perforatum) Desvenlafaxine
Lithium Duloxetine
Monoamine oxidase inhibitors (MAOIs) Venlafaxine
Moclobemide Tryptophan
Phenelzine
Tranylcypromine
ERRNVPHGLFRVRUJ
The severe life-threatening form most commonly develops after
deliberate self-poisoning with multiple serotonergic medications,
especially a selective serotonin reuptake inhibitor (SSRI) in
combination with a monoamine oxidase inhibitor (MAOI). Life-
threatening serotonin syndrome does not develop after ingestion of
single SSRIs.
DIFFERENTIAL DIAGNOSIS
Careful consideration of drug history, clinical features and clinical course
is essential to distinguish serotonin syndrome from neuroleptic malignant
syndrome, anticholinergic syndrome and malignant hyperthermia (see
Table 2.8.3). Other differential diagnoses include CNS infections and
intoxication with salicylates, theophylline, nicotine or sympathomimetic
agents.
MANAGEMENT
Resuscitation 73
• Attention to airway, breathing and circulation is paramount. If

there is coma, recurrent seizures, hyperthermia greater than 39.5°C
TOXICOLOGY HANDBOOK
or severe rigidity compromising ventilation, proceed to rapid
sequence intubation and ventilation while continuing with the
steps below.
• Administer oxygen.
• Check bedside blood glucose level.
• Check temperature. A temperature >38.5°C is an indication for
continuous core-temperature monitoring. A temperature >39.5°C is
an emergency and requires prompt intervention with neuromuscular
paralysis, intubation and ventilation to prevent further muscle-
generated heat production and severe hyperthermia leading to
multiple organ failure, neurological injury and death.
• Give titrated intravenous benzodiazepines (e.g. diazepam 5–10 mg;
children 0.1–0.3 mg/kg/dose over 3–5 minutes) to achieve gentle
sedation.
• Hypertension and tachycardia usually respond satisfactorily to
benzodiazepines given to achieve sedation. If refractory, a short-
acting intravenous infusion of a vasodilator such as GTN or sodium
nitroprusside is commenced and titrated to effect.
Risk assessment
Mild serotonin syndrome (normal mental status and vital signs) is a
self-limiting condition. Complete resolution over a period of hours is
anticipated.
ERRNVPHGLFRVRUJ
74
74
TABLE 2.8.3 Differential diagnosis of serotonin syndrome
Vital Bowel Neuromuscular

Condition Drug history Cadence signs Pupils Skin sounds tone Reflexes Mental status
Serotonin 5HT2A or 5HT1A <12 ↑HR, Mydriasis Sweaty Hyperactive Increased, esp. Hyperreflexia Agitation
syndrome agonist hours BR lower limbs and progressing
RR clonus to coma
and
Temp
Neuroleptic Dopamine Days ↑HR, Mydriasis Sweaty but Normal Lead-pipe Bradyreflexia Mutism, staring,
malignant antagonist BR or pale rigidity bradykinesia,
syndrome RR normal coma
and
Temp
Anticholinergic Anticholinergic <12 ↑HR, Mydriasis Hot, red Decreased Normal Normal Agitated delirium
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syndrome agent hours BR and dry or
RR absent
and
Temp
Malignant Inhalational Minutes– ↑HR, Normal Sweaty and Decreased Generalised Hyporeflexia Agitation
hyperthermia anaesthetic 24 hours BR mottled rigidity
RR
and
Temp
Adapted from Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine 2005; 352(11):1112–1120.
More severe forms of serotonin syndrome are potentially life-
threatening if not recognised and treated promptly. This complication
should be anticipated and specifically observed for following deliberate
self-poisoning with multiple serotonergic medications, especially an
MAOI in combination with an SSRI.
Investigations
In the context of deliberate self-poisoning, screening tests (paracetamol
level, BGL and 12-lead ECG) are indicated.
Depending on severity, further investigations including creatine
kinase, electrolytes, renal function tests and troponin may be required to
exclude significant complications.
Supportive care
• Cease causative agent(s).
• Reassure.
• Give intravenous fluids and monitor fluid balance. 75
• Carefully observe vital signs, including temperature, mental status

and muscle tone, until clinical improvement documented.
•
TOXICOLOGY HANDBOOK
Sedate with benzodiazepine as required.
Antidote therapy: Specific serotonin antagonists

There may be a role for specific serotonin antagonists in the management
of mild–moderate serotonin syndrome, refractory to benzodiazepine
administration. A number of serotonin antagonists have been used to
treat serotonin syndrome although their efficacy has not been established
in controlled trials. Cyproheptadine, an antihistamine with anti-
serotonergic effects (see Chapter 4.3: Cyproheptadine), can be given
orally, or via a nasogastric tube if tablets are crushed. The initial dose is
8 mg. If a clinical response is observed, further doses of 8 mg may be
repeated every 8 hours for the next 24 hours. Alternative agents –
particularly indicated if agitation is a prominent feature – are olanzapine
5–10 mg SL or chlorpromazine (25–100 mg given in 100 mL of normal
saline IV over 30–60 minutes). Adverse effects are common with
chlorpromazine and include significant sedation, orthostatic hypotension
and anticholinergic side effects.
Serotonin antagonists are not indicated for severe serotonin syndrome
where a good outcome can only be achieved with timely institution of
aggressive supportive care including cooling, endotracheal intubation,
ventilation and neuromuscular paralysis.
Disposition
The patient with mild serotonin syndrome related to therapeutic drug
administration may be discharged once the offending agent is ceased.
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They should be advised of the adverse effect and appropriate
arrangements made for review of their pharmacotherapy.
Patients at risk of developing serotonin syndrome following
deliberate self-poisoning should be observed for this complication for at
least 8 hours (12 hours if a slow-release preparation is ingested) and
never discharged overnight.
Any patient with altered mental status or vital signs requires

admission for observation, supportive care and consideration of a trial of
serotonin antagonist therapy. The duration of admission will usually be
less than 24 hours.
Patients who develop severe serotonin syndrome requiring
neuromuscular paralysis, intubation and ventilation are admitted to an
intensive care unit. Resolution of the syndrome with complete recovery
can be anticipated within 24–48 hours.
References
76 Boyer EW, Shannon M. The serotonin syndrome. New England Journal of Medicine
2005; 352(11):1112–1120.
76
Dunkley EJ, Isbister GK, Sibbritt D et al. The Hunter Serotonin Toxicity Criteria:
simple and accurate diagnostic decision rules for serotonin toxicity. Quarterly
TOXICOLOGY HANDBOOK
Journal of Medicine 2003; 96:635–642.

Isbister GK, Buckley NA, Whyte IM. Serotonin toxicity: a practical approach to
diagnosis and treatment. Medical Journal of Australia 2007; 187(6):361–365.
2.9 ANTICHOLINERGIC SYNDROME

Anticholinergic (antimuscarinic) syndrome arises due to competitive
inhibition of central and peripheral acetylcholine muscarinic receptors
and is potentially life threatening.
CLINICAL FEATURES
Anticholinergic syndrome is best characterised as an agitated delirium
associated with variable signs of peripheral muscarinic blockade (see
Table 2.9.1).
The diagnosis of anticholinergic syndrome is clinical, usually based
on the characteristic appearance of the delirium, the presence of some
peripheral signs and a history of ingestion of a known anticholinergic
agent (see Table 2.9.2). Signs and symptoms are variable and no particular
pattern of central or peripheral signs reliably diagnoses the syndrome.
Many anticholinergic pharmaceuticals and plants also have other toxic
effects, which may obscure or modify the anticholinergic aspect of their
clinical presentation in poisoning. If a clear history of ingestion is not
forthcoming, a differential diagnosis should be considered (see Table 2.9.3).
Focal neurological signs do not occur as part of the syndrome and their
presence prompts immediate investigation for an alternative diagnosis.
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TABLE 2.9.1 Clinical features of anticholinergic syndrome
Central Peripheral
Agitated delirium characterised by: Mydriasis

● Fluctuating mental status Tachycardia
● Confusion Dry mouth
● Restlessness Dry skin
● Fidgeting Flushing
● Visual hallucinations Hyperthermia
● Picking at objects in the air Sparse or absent bowel sounds
● Mumbling slurred speech Urinary retention
● Disruptive behaviour
Tremor
Myoclonus
Coma
Seizures (rare)
77
TOXICOLOGY HANDBOOK
TABLE 2.9.2 Anticholinergic agents
Antiparkinsonian drugs Atypical antipsychotic agents

Amantadine Olanzapine
Benztropine Quetiapine
Antihistamines Anticonvulsant agents
Brompheniramine Carbamazepine
Chlorpheniramine Motion sickness agents
Cyproheptadine Hyoscine-scopolamine
Dexchlorpheniramine Meclizine
Dimenhydrinate Antimuscarinic agents
Diphenhydramine Atropine
Doxylamine Hyoscine
Pheniramine Glycopyrrolate
Promethazine Topical ophthalmological agents
Trimeprazine Cyclopentolate
Antitussives Homatropine
Dextromethorphan Tropicamide
Antidepressants Urinary antispasmodic agents
Tricyclic antidepressants Oxybutynin
Antipsychotic agents Muscle relaxants
(butyrophenones and Cyclobenzaprine
phenothiazines) Orphenadrine
Chlorpromazine Plants and herbal remedies
Droperidol Selected mushrooms
Fluphenazine Datura species
Haloperidol Numerous other plant-derived
Thioridazine compounds
Trifluoperazine
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TABLE 2.9.3 Differential diagnosis of anticholinergic syndrome
Encephalitis Neurotrauma
Hypoglycaemia Sepsis
Hyponatraemia Serotonin syndrome
Ictal phenomenon Subarachnoid haemorrhage
Neuroleptic malignant syndrome Wernicke’s encephalopathy
When inadequately managed, patients with anticholinergic syndrome

are at risk of a number of complications that significantly affect their
clinical course. These include:
• Injury to themselves or others

• Dehydration
• Hyperthermia
• Rhabdomyolysis
• Pre-renal failure
78
• Pulmonary aspiration and atelectasis.
78
In the patient who presents late to medical care, some or all of these
TOXICOLOGY HANDBOOK
complications may already be present.
MANAGEMENT
Resuscitation
• Attention to airway, breathing and circulation.
• Detect and correct seizures (give benzodiazepines).
• Detect and correct hypoglycaemia.
• Detect and correct hyperthermia.
Risk assessment
The development of anticholinergic syndrome is anticipated following
deliberate self-poisoning with potent anticholinergic agents. It usually
manifests within the first few hours of ingestion. Once established, it is
difficult to predict the duration of delirium but it may persist for up to
5 days in some circumstances, such as deliberate self-poisoning with
benztropine or carbamazepine.
Supportive care
• Manage in a quiet but well-lit area.
• Reassure patient.
• Intravenous fluid resuscitation and maintenance. Patients are
frequently unable to drink and may already be dehydrated at
presentation.
• Insert an indwelling urinary catheter if any evidence of urinary
retention.
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• Treat agitation with diazepam 5–10 mg (0.1 mg/kg in children) PO
or IV every 10–15 minutes until the patient is resting quietly but able
to be roused easily. Repeat doses are often required but beware
over-sedation, as pulmonary atelectasis and/or aspiration are frequent
complications of prolonged sedation. Diazepam is the preferred
benzodiazepine because its longer duration of action more closely
matches the duration of delirium.
• One-on-one nursing is frequently necessary to maintain adequate
levels of supervision, reassurance and sedation.
• Avoid using drugs with known anticholinergic effects (e.g.
haloperidol, chlorpromazine).
Investigations
• Screening tests (12-lead ECG, BGL and serum paracetamol) if
deliberate self-poisoning is suspected. Also check a paracetamol level
in accidental paediatric poisoning if anticholinergic syndrome could
be due to an over-the-counter paracetamol-containing combination 79
cough or cold preparation.
• Specific testing as dictated by the individual agent (e.g.
TOXICOLOGY HANDBOOK
carbamazepine levels).
• Electrolytes and renal function.
• Creatine kinase.
• Consider further investigations to address the differential diagnosis.
Decontamination
The need for gastrointestinal decontamination is determined by a
risk–benefit analysis guided by the individual risk assessment.
The need for enhanced elimination is determined by a risk–benefit
analysis guided by the individual risk assessment.
Antidotes
Physostigmine is a centrally acting acetylcholinesterase inhibitor that
may be used to reverse anticholinergic delirium in selected patients,
particularly where it proves difficult to achieve adequate sedation with
titrated benzodiazepines. It sometimes also proves useful to confirm the
diagnosis of anticholinergic delirium and avoid the need for further
investigation to exclude alternative diagnoses. For further details on this
antidote, see Chapter 4.21: Physostigmine.
References
Liang HK. Clinical evaluation of the poisoned patient and toxic syndromes. Clinical
Chemistry 1996; 42(8):1350–1355.
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Patel RJ, Saylor T, Williams SR et al. Prevalence of autonomic signs and symptoms
in antimuscarinic drug poisonings. Journal of Emergency Medicine 2004;
26(1):89–94.
2.10 CHOLINERGIC SYNDROME

The cholinergic syndrome is the result of increased acetylcholine activity

at central and peripheral muscarinic and nicotinic receptors and is
potentially lethal. Acetylcholine is the neurotransmitter at pre- and
post-ganglionic parasympathetic, pre-ganglionic sympathetic and somatic
nerves. It is also an important neurotransmitter in the CNS. Cholinergic
syndrome arises from either acetylcholinesterase enzyme inhibition or
direct agonist action at muscarinic or nicotinic receptors.
Most cases of clinically significant cholinergic syndrome are due to
poisoning from organophosphate or carbamate pesticides. A
comprehensive list of causative agents is shown in Table 2.10.1.
80
CLINICAL FEATURES
80
Excessive stimulation of cholinoreceptors produces a constellation of

TOXICOLOGY HANDBOOK
CNS, autonomic and neuromuscular effects (see Table 2.10.2).
TABLE 2.10.1 Cholinergic syndrome: causative agents

ACETYLCHOLINESTERASE INHIBITORS
Organophosphate insecticides Chemical warfare nerve agents

Chlorpyrifos Tabun (GA)
Coumafos Sarin (GB)
Diazinon Soman (GD)
Dimethoate VX
Fenthion Agents used in dementia
Malathion Donepezil
Carbamate insecticides Galantamine
Aldicarb Rivastigmine
Arasan Tacrine
Cycloate Agents used in myasthenia gravis
Terbucarb Edrophonium
Thiram Neostigmine
Physostigmine
Pyridostigmine
ACETYLCHOLINE AGONISTS
Muscarinic agents Nicotinic agents

Acetylcholine Nicotine (tobacco, gums,
Bethanechol patches)
Carbachol Mushrooms
Pilocarpine
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TABLE 2.10.2 Clinical features of cholinergic syndrome
Central Sympathetic
nervous Parasympathetic nicotinic
system Neuromuscular muscarinic effects effects
Agitation Fasciculation Abdominal cramping Hypertension
Central Muscle weakness Bradycardia Mydriasis
respiratory Bronchoconstriction Sweating
depression Bronchorrhoea Tachycardia
Coma Diarrhoea
Confusion Lacrimation
Lethargy Miosis
Seizures Salivation
Urinary incontinence
Vomiting
TABLE 2.10.3 Differential diagnosis of cholinergic syndrome 81
Causes of weakness (neurotoxic snakebite, Guillain-Barré syndrome,
TOXICOLOGY HANDBOOK
myasthenia gravis, botulism)
Cardiotropic intoxication resulting in bradycardia and vomiting (digoxin,
oleander, beta-adrenergic blockers, calcium channel blockers)
Gastroenteritis and abdominal emergencies
Ictal phenomena
Mushroom ingestion
Respiratory disorders (asthma, congestive cardiac failure)
Salicylate intoxication
Serotonin syndrome
Sympathomimetic syndrome
Theophylline intoxication
Classically, the patient in cholinergic crisis has copious secretions,

vomiting, diarrhoea and altered mental status. Fasciculation and muscle
weakness may be prominent. Death is secondary to respiratory failure
from excessive respiratory secretions and weakness of ventilatory
muscles.
Signs and symptoms are variable. Although bradycardia secondary to
increased vagal tone is expected, tachycardia is very common secondary
to hypoxia, peripheral vasodilation and the effects of nicotinic stimulation.
The diagnosis is clinical and based on the characteristic clinical
features and progress, usually supported by an exposure history. Miosis
appears to be a consistent feature of chemical warfare nerve agent
poisoning. Laboratory testing is useful to exclude other diagnoses (see
risk assessment below and Table 2.10.3) or complications. Complications
may include:
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• Rapid onset of respiratory failure
• Seizures
• Dehydration
• Medium- and long-term neurological sequelae of organophosphate
intoxication.
MANAGEMENT
Resuscitation
In the setting of insecticide poisoning, efforts to decontaminate the
patient or use sophisticated personal protective equipment should not
delay resuscitation efforts.
• Attention to airway, breathing and circulation is paramount. Early

control of pulmonary secretions and administration of oxygen is the
key to survival.
• Give supplemental oxygen.
82
• Administer atropine if there are any objective signs of muscarinic
excess, such as cough, dyspnoea, respiratory failure, vomiting,
82
diarrhoea, salivation, lacrimation or bradycardia. Repeated escalating

TOXICOLOGY HANDBOOK
doses are given (see Chapter 4.1: Atropine) until drying of respiratory
secretions is achieved.
• Control seizures with benzodiazepines.
• If adequate oxygenation and ventilation are not rapidly achieved with
oxygen and atropine, proceed immediately to intubation and
ventilation.
Risk assessment
The risk assessment for cholinergic syndrome depends on the underlying
cause. Deliberate self-poisoning with any organophosphate agent is
expected to lead to a life-threatening cholinergic crisis. Any ingestion of
an organophosphate agent by a child is also regarded as potentially life
threatening. The need for large doses of atropine should be anticipated.
If a clear history of ingestion is not forthcoming, a differential diagnosis
should be considered (see Table 2.10.3).
Supportive care
• In insecticide poisoning, staff should manage the patient in a
well-ventilated room using universal precautions. Sophisticated
personal protective equipment is not required.
• Commence fluid resuscitation. Patients may already be dehydrated at
presentation and require intravenous fluid resuscitation. Increased
insensible fluid losses are likely and often patients cannot drink, so
ongoing intravenous fluid management is frequently required.
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• Insert an indwelling catheter. Monitor fluid balance until the patient
is drinking normally.
Investigations
• Screening tests (12-lead ECG, BGL and serum paracetamol level)
indicated if deliberate self-poisoning is suspected
• Specific testing as dictated by the individual agent (e.g.
cholinesterase levels)
• Chest X-ray
• Arterial blood gases
• Electrolytes and renal function
• Consider further testing to address the differential diagnosis
Decontamination
The need for gastrointestinal decontamination is determined by a
risk–benefit analysis that incorporates the risk assessment. In the setting
of insecticide poisoning, efforts to decontaminate the patient or use 83
sophisticated personal protective equipment should not delay
resuscitation efforts.
TOXICOLOGY HANDBOOK
The need for enhanced elimination will be determined by a risk–benefit
analysis that incorporates the risk assessment.
Antidotes
Atropine (see Chapter 4.1: Atropine).
The utility of pralidoxime (see Chapter 4.22: Pralidoxime) for
organophosphate or nerve agent intoxication is controversial.
References
Liang HK. Clinical evaluation of the poisoned patient and toxic syndromes. Clinical
Chemistry 1996; 42(8):1350–1355.
Little M, Murray L. Consensus statement: risk of nosocomial organophosphate
poisoning in emergency departments. Emergency Medicine Australasia 2004;
16:456–458.
Eddleston M, Dawson A, Karalliedde L et al. Early management after self-poisoning
with an organophosphorus or carbamate insecticide: a treatment protocol for
junior doctors. Critical Care 2004; 8(6):R391–R397.
2.11 NEUROLEPTIC MALIGNANT SYNDROME

Neuroleptic malignant syndrome (NMS) is a rare but potentially lethal
syndrome complicating the use of neuroleptic medications. It is
characterised by neuromuscular rigidity, altered mental status and
autonomic instability.
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TABLE 2.11.1 Clinical features of neuroleptic malignant syndrome
Central nervous Autonomic

system instability Neuromuscular
Confusion Hyperthermia ‘Lead-pipe’ rigidity

Delirium Tachycardia Generalised bradykinesia or
Stupor Hypertension akinesia

Coma Respiratory Mutism and staring
irregularities Dysarthria
Cardiac dysrhythmias Dystonia and abnormal postures
Abnormal involuntary
movements
Incontinence
The aetiology of NMS remains controversial. Although a central

deficiency of dopaminergic neurotransmission at nigrostriatal,
84 mesolimbic and hypothalamic–pituitary pathways appears pivotal,
peripheral mechanisms involving altered skeletal muscle mitochondrial
84
function may also be involved. The syndrome develops in 0.02–2.5%

TOXICOLOGY HANDBOOK
of patients taking neuroleptic medication and this incidence does not

appear to have changed significantly with the introduction of atypical
antipsychotics into clinical practice.
CLINICAL FEATURES
The syndrome is characterised by altered mental status, autonomic
instability and neuromuscular dysfunction (see Table 2.11.1). The onset
of NMS typically occurs over 24–72 hours. Recovery may take many
days to months.
DIAGNOSTIC CRITERIA
The diagnosis is clinical, based on a high index of suspicion, presence of
characteristic signs and symptoms and the history of ingestion of one or
more neuroleptic agents. Neuroleptic malignant syndrome is a clinical
diagnosis made after other medical conditions have been considered and
excluded as necessary.
Strict criteria have been proposed but they may lack sensitivity in
milder cases (see Table 2.11.2).
Leucocytosis, ranging up to 40 000 cells/microL, is common.
Alterations of hepatic and renal function, metabolic acidosis,
hypocalcaemia, hypomagnesaemia and decreased serum iron may also be
seen. Cranial CT and MRI are normal. Lumbar puncture, usually
performed to exclude encephalitis, may show elevated CSF protein in up
to 37% of cases. Generalised slow wave activity, consistent with a
metabolic encephalopathy, is seen on electroencephalogram (EEG).
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TABLE 2.11.2 Criteria for diagnosis of NMS
● Recent exposure to dopamine antagonist, or dopamine agonist

withdrawal
● Hyperthermia
● Rigidity
● Mental status alteration
● CK elevation (at least 4 times upper limit of normal)
● Sympathetic nervous system lability, defined as at least two of the
following:
— Blood pressure elevation (systolic or diastolic >25% above baseline)
— Blood pressure fluctuation (>20 mmHg diastolic change or
>25 mmHg systolic change within 24 hours)
— Diaphoresis
— Urinary incontinence
● Tachycardia plus tachypnoea
● Negative work-up for infectious, toxic, metabolic and neurological causes
Adapted from Gurrera RJ, Caroff SN, Cohen A et al. An international consensus study
of neuroleptic malignant syndrome diagnostic criteria using the Delphi method.
Journal of Clinical Psychiatry 2011; 72:1222–1228. 85
The following risk factors for NMS have been suggested:
TOXICOLOGY HANDBOOK
• High doses of neuroleptic agent
• Increased dose of neuroleptic agent within the previous 5 days
• Large magnitude dosage increase
• Parenteral administration
• Simultaneous use of two or more neuroleptic agents
• Use of haloperidol or depot fluphenazine
• Young age
• Male sex
• Psychiatric co-morbidity
• Genetic factors
• Pre-existing organic brain disorders (infectious encephalitis, AIDS,
tumours)
• Dehydration
• High CK levels during episodes of psychosis not associated with NMS
• Other pre-existing medical disorders (trauma, infection, malnutrition,
premenstrual phase, thyrotoxicosis).
Neuroleptic malignant syndrome is a diagnosis of exclusion and the
following important alternative diagnoses that share some general
features with NMS must be considered:
• Acute lethal (malignant) catatonia

• Malignant hyperthermia
• Serotonin syndrome (see Chapter 2.8: Serotonin syndrome)
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• Anticholinergic syndrome (see Chapter 2.9: Anticholinergic syndrome)
• Sympathomimetic syndrome
• Encephalitis
• Metabolic encephalopathies.
The clinical features of NMS are compared with those of serotonin
syndrome, anticholinergic syndrome and malignant hyperthermia in

Table 2.8.3.
Acute lethal (malignant) catatonia is clinically very similar to NMS.
The diagnostic criteria are nearly identical but NMS is distinguished by
a history of recent antipsychotic medication use. Neuroleptic malignant
syndrome is usually characterised by bradykinesia and mutism, whereas
acute lethal catatonia may be characterised by abnormal posturing and
waxy flexibility.
COMPLICATIONS
86 • Respiratory failure
• Dehydration
86
• Renal failure
•
TOXICOLOGY HANDBOOK
Multiple-organ failure
• Thromboembolism
• Residual catatonia and parkinsonian symptoms
• Recurrence after rechallenge with an antipsychotic agent may occur
in 30–50% of patients who suffer NMS
MANAGEMENT
Resuscitation
• Attention to airway, breathing and circulation is paramount. If there
is coma, hyperthermia >39.5°C or severe rigidity compromising
ventilation, proceed to rapid-sequence intubation and ventilation
while continuing with the steps below.
• Administer oxygen.
• Detect and correct hyperthermia. A temperature >38.5°C is an
indication for continuous core-temperature monitoring. A temperature
>39.5°C is an emergency and requires prompt intervention with
neuromuscular paralysis, intubation and ventilation to prevent further
muscle-generated heat production, and severe hyperthermia leading
to multiple-organ failure, neurological injury and death.
• Avoid any agent with dopamine antagonist effects.
• Intravenous benzodiazepines are controversial in the management of
NMS. They are frequently used to achieve muscle relaxation and
control of delirium in mild-to-moderate cases (e.g. diazepam
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5–10 mg over 3–5 minutes titrated to achieve gentle sedation).
However, because benzodiazepines may play a role in the aetiology
of NMS, more specific agents such as bromocriptine are preferred in
severe cases.
• Hypertension and tachycardia may initially be treated with a
parenteral vasodilator such as GTN or sodium nitroprusside.
Bromocriptine (see below) is indicated if there is significant
autonomic instability.
Investigations
Depending on severity, further investigations may be required to exclude
alternative diagnoses and detect significant complications:
• Chest X-ray
• 12-lead ECG
• Full blood count
• Renal function and electrolytes 87
• Creatine kinase
• Serum calcium and magnesium
•
TOXICOLOGY HANDBOOK
Liver function tests
• Blood and urine cultures
• Cranial CT
• Lumbar puncture
• MRI brain
• Electroencephalogram.
Supportive care
• Cease causative agent(s).
• Administer intravenous fluids and institute fluid balance monitoring.
• Monitor temperature.
• In mild-to-moderate cases, supplemental benzodiazepine sedation
may be indicated.
• Consider thromboembolism prophylaxis.
Antidote therapy
The roles of bromocriptine, dantrolene and electroconvulsive therapy
(ECT) have not been defined by prospective trials. It is not known
whether they increase survival or shorten the clinical course when
compared with good supportive care alone.
Bromocriptine is a dopamine agonist that may be given orally or via
a nasogastric tube. It is indicated in moderate and severe cases. Dosing
commences at 2.5 mg every 8 hours, increasing to 5 mg every 4 hours
ERRNVPHGLFRVRUJ
(30 mg/day). Adverse effects include postural hypotension, headache,
nausea, vomiting, dyskinesia and erythromelalgia (painful erythematous
lower limbs). Autonomic instability and fever usually improve within 24
hours of commencing bromocriptine therapy but neuromuscular changes
and delirium may take longer to resolve (1–2 days and several days,
respectively). If bromocriptine is used, it should be continued for 1–2
weeks before tapering the dose.

Dantrolene is indicated if there is severe muscle rigidity and fever.
It is administered intravenously 2–3 mg/kg/day up to a total dose of
10 mg/kg/day. Once oral treatment can be tolerated, it may be given in
an oral dose of 100–400 mg/day in divided doses for 10 days, or the
patient may be switched to bromocriptine.
Electroconvulsive therapy (ECT) has been reported to improve fever,
sweating and consciousness level in some patients. It is thought to act by
increasing central dopaminergic activity. Improvement may be seen after
the third or fourth treatment. It has been advocated for:
88
• Severe NMS refractory to supportive care and antidote treatment
•
88
Severe NMS that is difficult to differentiate from acute lethal catatonia

• Treatment of residual catatonic symptoms after NMS
TOXICOLOGY HANDBOOK
• When the psychiatric disorder underlying severe NMS is psychotic

depression or catatonia.

Following cessation of the causative agent, patients with normal mental
status (no delirium or seizures) and normal vital signs may be reassured
and considered for discharge following a period of observation (e.g. 12
hours). An oral benzodiazepine (e.g. diazepam 5 mg 6–8 hourly) may be
used for symptomatic treatment for 24 hours.
Other patients usually require admission for further supportive care
with or without specific antidote treatment.
The patient should be advised of the adverse effect or drug
interaction prior to discharge and subsequent psychopharmacotherapy
will need careful review. Recurrence after rechallenge with an
antipsychotic agent may occur in 30–50% of patients who suffer NMS.
References
Bhanushali MJ, Tuite PJ. The evaluation and management of patients with neuroleptic
malignant syndrome. Neurology Clinics of North America 2004; 22:389–411.
Gurrera RJ, Caroff SN, Cohen A et al. An international consensus study of neuroleptic
malignant syndrome diagnostic criteria using the Delphi method. Journal of
Clinical Psychiatry 2011; 72:1222–1228.
Rusyniak DE, Sprague JE. Toxin-induced hyperthermic syndromes. Medical Clinics of
North America 2005; 89:1277–1296.
Trollor JN, Chen X, Sachdev PS. Neuroleptic malignant syndrome associated with
atypical antipsychotic drugs. CNS Drugs 2009; 23(6):477–492.
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2.12 ALCOHOL USE DISORDER
Alcohol abuse and dependence is formally defined as alcohol use
disorder (AUD) (see Box 2.12.1). Alcohol withdrawal is a potentially
life-threatening medical condition.
More harm occurs in the community as a result of the acute health
and social effects of alcohol use than from the consequences of long-
term alcohol dependence (see Table 2.12.1). Upwards of 30% of all
emergency department presentations are alcohol-related. The incidence
BOX 2.12.1 Psychiatric definition of alcohol use disorder (DSM-V)

● Alcohol is often taken in larger amounts or over a longer period than
was intended.
● There is a persistent desire or unsuccessful efforts to cut down or
control alcohol use. 89
● A great deal of time is spent in activities necessary to obtain alcohol,
use alcohol or recover from its effects.
TOXICOLOGY HANDBOOK
● Craving or a strong desire or urge to use alcohol occurs.
● Recurrent alcohol use results in a failure to fulfil major role obligations
at work, school or home.
● Alcohol use continues despite having persistent or recurrent social or
interpersonal problems caused or exacerbated by the effects of alcohol.
● Important social, occupational or recreational activities are given up or
reduced because of alcohol use.
● Recurrent alcohol use occurs in situations in which it is physically
hazardous.
● Alcohol use is continued despite knowledge of having a persistent or
recurrent physical or psychological problem that is likely to have been
caused or exacerbated by alcohol.
● Tolerance occurs, as defined by either of the following:
— A need for markedly increased amounts of alcohol to achieve
intoxication or desired effect
— A markedly diminished effect with continued use of the same
amount of alcohol.
● Withdrawal occurs, as manifested by either of the following:
— The characteristic withdrawal syndrome for alcohol
— Alcohol (or a closely related substance, such as a benzodiazepine)
is taken to relieve or avoid withdrawal symptoms.
The presence of a least 2 of these symptoms indicates an alcohol use
disorder (AUD).
The severity of AUD is defined as:
● Mild: the presence of 2 to 3 symptoms
● Moderate: the presence of 4 to 5 symptoms
● Severe: the presence of 6 or more symptoms.
Adapted from Diagnostic and Statistical Manual of Mental Disorders. 5th edn.
Arlington, Virginia: American Psychiatric Association; 2013.
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TABLE 2.12.1 Medical complications of chronic alcohol abuse
Cardiovascular Malignancy
Atrial fibrillation Breast
Cardiomyopathy Colorectal
Electrolytes Hepatic
Hypocalcaemia Larynx
Hypokalaemia Oesophagus
Hypomagnesaemia Oropharynx
Hypophosphataemia Malnutrition
Endocrine Folate deficiency
Hypoglycaemia Niacin deficiency (pellagra)
Hypogonadism Stomatitis
Osteoporosis Vitamin C deficiency (scurvy)
Steatosis Neurological
Haematological Dementia
Anaemia Cerebellar degeneration
Coagulopathy Korsakoff’s syndrome
Leucopenia Peripheral neuropathy
90 Macrocytosis Wernicke’s encephalopathy
Thrombocytopenia Psychiatric
90
Gastrointestinal Alcoholic hallucinosis

Alcoholic hepatitis Depression and suicide
TOXICOLOGY HANDBOOK
Cirrhosis Delusions
Gastritis
Malabsorption
Oesophageal varices and
gastrointestinal haemorrhage
Pancreatitis
Adapted from Sivilotti ML. Ethanol, isopropanol and methanol. In: Dart RC, ed.
Medical Toxicology. 3rd edn. Philadelphia: Lippincott Williams & Wilkins; 2003.
of alcohol-related problems is even higher in the population that presents

to emergency departments with deliberate self-poisoning with either
self-harm or recreational intent.
SCREENING AND BRIEF INTERVENTION STRATEGIES

Presentation to the emergency department, particularly with acute
poisoning, provides an ideal opportunity to identify individuals with
alcohol-related problems and provide brief intervention with the aim of
improving long-term outcomes.
In most settings, doctors identify fewer than 50% of patients with
alcohol-related problems. Factors associated with failure to identify these
individuals include:
• Inadequate training about substance abuse

• Negative attitudes towards patients with substance abuse
• Scepticism about effectiveness of treatments
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• Belief that alcohol problems are not in the realm of the generalist
clinician
• Excessive time required to perform formal screening procedures.
A number of tools have been developed to assist identification
of potentially hazardous alcohol consumption and are suitable for
application in the emergency department. The Alcohol Use Disorders
Identification Test (AUDIT) identifies patients with at-risk, hazardous
or harmful drinking with a sensitivity of 51–97% and a specificity of
78–96% (see Box 2.12.2). The ‘CAGE’ questions detect alcohol abuse
and dependence with a sensitivity of 43–94% and specificity of 70–97%
(see Box 2.12.3).
The following single question when administered to trauma patients,
using a cut-off of three drinks, correlates well with the AUDIT score:
‘On a typical day when you are drinking, how many drinks do you
have?’ Abbreviated screening tools such as this consume minimal time
and do not require detailed training. 91
Early detection of alcohol problems allows implementation of
brief intervention strategies such as ‘FRAMES’, which has been
shown to decrease alcohol consumption in non-dependent patients (see
TOXICOLOGY HANDBOOK
Box 2.12.4).
ALCOHOL WITHDRAWAL
The alcohol withdrawal syndrome usually develops within 6–24 hours of
cessation or reduction in alcohol consumption in dependent individuals.
It commonly develops in patients admitted to hospital.
Pathophysiology
Ethanol dependence affects multiple neurotransmitter systems.
Down-regulation of neuro-inhibitory GABA receptors leads to symptoms
of GABA excess in withdrawal. Alcohol also inhibits the excitatory
NMDA glutamate receptor and withdrawal abruptly removes this
inhibition. Increased dopaminergic and noradrenergic neurotransmission
also occur.
Clinical features
Alcohol withdrawal manifests as a constellation of clinical autonomic
and neurological features with a wide spectrum of severity and a typical
time course.
Autonomic excitation
• Occurs within hours of cessation and peaks at 24–48 hours
— Tremor
— Anxiety and agitation
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92
92
BOX 2.12.2 The Alcohol Use Disorders Identification Test (AUDIT) Score (WHO 1992)
Questions pertain to behaviour in the last year
Score 0 1 2 3 4
How often do you have a drink containing alcohol? Never Monthly Two to Two to Four or
or less four times three times more times
per month per week per week
How many drinks containing alcohol do you have on a typical 1 or 2 3 or 4 5, 6 or 7 8 or 9 10 or more

day when you are drinking?
How often do you have 6 or more drinks on one occasion? Never Less than Monthly Weekly Daily or
monthly almost daily
ERRNVPHGLFRVRUJ
How often during the last year have you found that you were Never Less than Monthly Weekly Daily or
not able to stop drinking once you had started? monthly almost daily
How often during the last year have you failed to do what Never Less than Monthly Weekly Daily or
was normally expected from you because of drinking? monthly almost daily
How often during the last year have you needed a first drink Never Less than Monthly Weekly Daily or
in the morning to get yourself going after a heavy drinking monthly almost daily
session?
Score 0 1 2 3 4
How often during the last year have you had a feeling of guilt Never Less than Monthly Weekly Daily or
or remorse after drinking? monthly almost daily
How often during the last year have you been unable to Never Less than Monthly Weekly Daily or
remember what happened the night before because you had monthly almost daily
been drinking?
Have you or someone else been injured as a result of your No Yes, but Yes, during
drinking? not in the the last
last year year
Has a relative or friend or doctor or other health worker been No Yes, but Yes, during
concerned about your drinking or suggested you cut down? not in the the last
last year year
Hazardous alcohol usage. Help required
ERRNVPHGLFRVRUJ
Score >20
Score 16–19 Hazardous alcohol usage. Help urged
Score 8–15 Drinking exceeding safe levels
Score 0–7 Normal usage

93
BOX 2.12.3 ‘CAGE’ questions
Two or more positive responses identify patients with lifetime risk of
alcohol problems.
Cut down: Have you ever tried to cut down your drinking?
Annoyed: Have you ever been annoyed by criticism of your drinking?
Guilty: Do you feel guilty about your drinking?

Eye-opener: Do you need an eye-opener when you get up in the morning?
BOX 2.12.4 ‘FRAMES’ acronym

Feedback: review problems caused by alcohol with the patient
Responsibility: point out that changing behaviour is the patient’s
responsibility
Advice: advise the patient to cut down or abstain from alcohol
94 Menu: provide options to assist the patient to change behaviour
Empathy: use an empathetic approach
94
Self-efficacy: encourage optimism that the patient can change behaviour

TOXICOLOGY HANDBOOK
— Sweating
— Tachycardia
— Hypertension
— Nausea and vomiting
— Hyperthermia
Neuro-excitation
• Occurs within 12–48 hours of cessation
— Hyperreflexia
— Nightmares
— Hallucinations (visual, tactile and occasionally auditory)
— Generalised tonic–clonic seizures
Delirium tremens
• Severe form with mortality approaching 8%
• Up to 20% of patients admitted to urban hospitals with alcohol
withdrawal
• Associated with medical co-morbidities and delayed presentation
— Hallucinations
— Confusion, disorientation and clouding of consciousness
— Autonomic hyperactivity
— Respiratory and cardiovascular collapse
— Death
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TABLE 2.12.2 Signs of Wernicke’s encephalopathy
Acute confusion
Reduced level of consciousness
Coma
Memory disturbance
Ataxia
Ophthalmoplegia
Nystagmus
Unexplained hypotension
Hypothermia
Co-morbidities
A number of important co-morbidities should be considered, detected
and managed in all patients with high or regular alcohol intake:
• Wernicke’s encephalopathy (see Table 2.12.2)

• Dehydration 95
• Hypoglycaemia
• Electrolyte abnormalities
• Coagulation disorders/thrombocytopenia
TOXICOLOGY HANDBOOK
• Anaemia, usually macrocytic
• Alcoholic gastritis and gastrointestinal bleeding
• Pancreatitis
• Alcoholic liver disease and hepatic encephalopathy
• Subdural haemorrhage
• Alcoholic ketoacidosis.
Management
Mild forms of alcohol withdrawal are managed with simple supportive
care in an outpatient setting. Symptoms typically settle in 2–7 days.
Relapse is common without implementation of adequate psychosocial
support.
Withdrawal in a residential setting with professional supervision with
or without medication is more appropriate in the following circumstances:
• History of severe alcohol withdrawal

• Poor social support
• Failure of unsupervised outpatient withdrawal.
Inpatient alcohol withdrawal is indicated for the minority of patients
in whom there is a significant risk of delirium tremens, seizures or
significant co-morbidities:
• Presentation with severe alcohol withdrawal

— Abnormal vital signs after initial treatment
— Hallucinations
ERRNVPHGLFRVRUJ
— Altered conscious state
— Seizures
• Presence of medical complications or co-morbidities (see above)
• Presence of significant psychiatric co-morbidities.
Management approach to severe alcohol withdrawal in the
hospital setting
Resuscitation, supportive care and monitoring
• Florid delirium tremens constitutes a medical emergency and is
managed in an area fully equipped for resuscitation and monitoring
with the following priorities:
— Immediate attention to airway, breathing and circulation
— Establishment of IV access
— Control of seizures and delirium by administration of repeated
doses of IV diazepam 5–10 mg until seizures and agitation are
controlled
96
— Detection and treatment of hypoglycaemia.
•
96
Alcohol withdrawal onset, severity, progress and response to therapy

is best monitored with an alcohol withdrawal chart incorporating an
TOXICOLOGY HANDBOOK
easily calculated alcohol withdrawal score (AWS) (see Box 2.12.5).

• Institute monitoring for alcohol withdrawal in any patient judged to
be at risk of developing alcohol withdrawal, not just patients who
present in established withdrawal.
• Give regular oral diazepam 5–20 mg PO as dictated by AWS to
maintain adequate control of withdrawal.
• Give thiamine 200 mg IV tds for the first 24 hours and then review.
This should be continued for 3 days if there is altered mental status
and even higher doses should be given if Wernicke’s encephalopathy
is strongly suspected (see Table 2.12.2).
• Ensure adequate hydration, electrolyte balance and nutrition.
• Detect and treat co-morbidities.
• Note: Phenytoin is not indicated in the treatment or prevention of
alcohol-related seizures.
Investigations as indicated
EUC, FBE, LFTs, coagulation profile, serum lipase
• Medical admission is indicated if:
— Large doses of diazepam are required to control withdrawal
— Medical co-morbidities require care.
• Referral to residential or home detoxification and rehabilitation
services for assessment and psychosocial support is considered once
acute withdrawal is controlled or resolving.
ERRNVPHGLFRVRUJ
BOX 2.12.5 Alcohol withdrawal score (AWS)
Orientation 0 – Orientated = The patient is fully orientated in
time, place and person
1 – Disorientated = Disorientated but cooperative
2 – Uncooperative = Disorientated and uncooperative
Agitation/ 0 – Calm = Rests normally
anxiety 1 – Anxious = Appears anxious
2 – Panicky = Appears very agitated all the
time, panics or gets out of bed
for no reason
Hallucination 0 – None = No evidence of hallucinations

1 – Anxious = Distortion of real objects or
hallucinations but accepted as
not real when pointed out
2 – Can’t dissuade = Believes the hallucinations are
real and cannot be reassured
97
Perspiration 0 – Nil = No abnormal sweating
1 – Moist/wet = Mild-to-moderate perspiration
2 – Soaking = Soaking sweat
TOXICOLOGY HANDBOOK
Tremor 0 – Nil = No tremor
1 – With intention = Tremor when moving hands and
arms
2 – At rest = Constant tremor of arms even at
rest
Temperature 0 – 37.5°C or less

1 – 37.6°C to 38.5°C
2 – >38.5°C
Adapted with permission from the Alcohol Withdrawal Chart at Sir Charles Gairdner
Hospital, Nedlands, Western Australia.
References
Friedman PD. Alcohol use in adults. The New England Journal of Medicine 2013;
368:365–373.
Hall W, Zador D. The alcohol withdrawal syndrome. Lancet 1997; 349:1897–1900.
Holmwood C. Alcohol related problems in Australia: is there a role for general
practice? Medical Journal of Australia 2002; 177:102–103.
Kosten TR, O’Connor PG. Management of drug and alcohol withdrawal. New England
Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995;
333(16):1058–1065.
Reed DN, Saxe A, Montanez M et al. Use of a single question to screen trauma
patients for alcohol dependence. Journal of Trauma 2005; 59:619–623.
Sechi GP, Serra A. Wernicke’s encephalopathy: new clinical settings and recent
advances in diagnosis and management. Lancet Neurology 2007; 6:442–455.
Tjipto AC, Taylor D McD, Liew H. Alcohol use among young adults presenting to the
emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
ERRNVPHGLFRVRUJ
2.13 AMPHETAMINE USE DISORDER
Amphetamine use disorder is defined by DSM-V along the lines of
substance use disorder in general as outlined for alcohol (see Box 2.12.1).
Life-time prevalence of stimulant use disorder is estimated at 3.3% and
peaks in 16–29-year-olds. Amphetamine and other stimulant-related

presentations represent a significant burden on emergency departments,
accounting for over 1% of all presentations. Most of these presentations
relate to medical, social and psychiatric sequelae of acute amphetamine
intoxication. The management of these presentations together with the
clinical toxicology of amphetamines is dealt with in Chapter 3.8:
Amphetamines and other sympathomimetics.
Long-term amphetamine abuse is associated with medical,
psychiatric and social sequelae (see Table 2.13.1). These sequelae may
result directly in hospital presentation or complicate the management of
98 intercurrent illness. Amphetamines, particularly methamphetamine, are
highly addictive and patients may also present in withdrawal or develop
98
withdrawal during admission for other reasons.

TOXICOLOGY HANDBOOK
No pharmacological agent has been demonstrated to be effective in

the treatment of amphetamine withdrawal, dependence or abuse.
Management relies on counselling and social support.
AMPHETAMINE WITHDRAWAL
Prolonged or heavy use of amphetamines results in tachyphylaxis
(reduced response to repeated doses). This phenomenon is thought to be
due to depleted concentrations of neurotransmitters. The symptoms are
largely psychiatric and mood-related, and include depression, fatigue,
insomnia, increased appetite and cognitive impairment. Symptoms
TABLE 2.13.1 Effects of long-term amphetamine abuse
Medical
Cardiomyopathy (rare)
Poor dentition
Weight loss
Psychiatric
Confusion
Emotional lability
Insomnia
Memory loss
Paranoia
Paranoid psychosis
Social
Damage to social relationships
Neglect of social, interpersonal and occupational responsibilities
ERRNVPHGLFRVRUJ
usually peak 2–4 days following cessation of use but may continue for
7–14 days. Amphetamine withdrawal in itself is rarely severe enough to
warrant medical admission. Management consists of referral for
appropriate psychosocial support.
References
Romanelli F, Smith KM. Clinical effects and management of amphetamines.
Pharmacotherapy 2006; 26(8):1148–1156.
Sara GE, Burgess PM, Harris MG et al. Stimulant use and stimulant use disorders in
Australia: findings from the national survey of mental health and wellbeing.
Medical Journal of Australia 2011; 195:607–610.
Shoptaw SJ, Kao U, Heinzerling K et al. Treatment for amphetamine withdrawal.
Cochrane Database of Systematic Reviews 2009; 2:C0003021.
Srisurapanont M, Jarusuraisin N, Krittirattanapaiboon P. Treatment for amphetamine
dependence and abuse. Cochrane Database of Systematic Reviews 2001;
4:C0003022.
2.14 OPIOID USE DISORDER 99
Opioid use disorder is defined by DSM-V along the lines of substance
TOXICOLOGY HANDBOOK
use disorder in general as outlined for alcohol (see Box 2.12.1). Opioid-
related presentations represent an increasing burden on the health system.
In particular, there has been a doubling of hospital admissions and deaths
related to prescription opioids in the past decade in Australia and the
United Kingdom. The management of these presentations together with
the clinical toxicology of opioids is dealt with in Chapter 3.57: Opioids.
OPIOID WITHDRAWAL
Opioid withdrawal syndrome is the physiological response that develops
when there is abrupt cessation or rapid reduction in opioid dose in a
dependent individual, or when that individual is administered an opioid
antagonist or partial agonist.
Pathophysiology
The opioids exert their analgesic effects by agonist activity at CNS µ
receptors. These mediate their effects by decreasing intracellular cAMP
via membrane-bound G-proteins. Prolonged opioid use leads to a process
of cellular adaptation and down-regulation through multiple mechanisms.
When opioids are ceased a withdrawal syndrome develops.
Clinical features
Although unpleasant, uncomplicated opioid withdrawal is not life
threatening. This is in contrast to withdrawal from alcohol or sedative-
hypnotics. The symptoms are usually sufficiently uncomfortable to
prompt efforts to obtain opioids by the individual concerned.
ERRNVPHGLFRVRUJ
The timing of onset of symptoms depends on the elimination
kinetics of the specific opioid, the usual dose ingested and the degree
of dependence. Symptoms may begin within 6 hours of the last heroin
dose, peak at 36–48 hours and resolve within 1 week. In contrast, onset
of symptoms may be delayed 2–3 days after cessation of methadone,
peak at several days and last for up to 2 weeks. Patients may present
with withdrawal symptoms associated with cessation of more than one

agent.
The clinical manifestations of opioid withdrawal include intense
craving, dysphoria, autonomic hyperactivity and gastrointestinal distress.
More specifically, symptoms include:
• Anxiety, restlessness and dysphoria

• Insomnia
• Intense craving
• Yawning
100 • Lacrimation
• Salivation
10
•
0
Rhinorrhoea
• Anorexia, nausea and vomiting
TOXICOLOGY HANDBOOK
• Abdominal cramps and diarrhoea

• Mydriasis
• Piloerection
• Diaphoresis
• Flushing
• Myalgia and arthralgia
• Hypertension and tachycardia in severe cases.
Altered mental status, delirium, hyperthermia and seizures do not
occur. Their presence should alert the clinician to an alternative
diagnosis or complication.
Co-morbidities
Co-morbidities that should be considered in patients with opioid
withdrawal include:
• Alcohol or sedative-hypnotic withdrawal syndrome

• Dehydration
• Infective complications of intravenous drug abuse
• Psychiatric morbidities.
Management
Administration of opioids in sufficient dose will abolish all physiological
manifestations of the withdrawal syndrome. Administration of opioids to
ERRNVPHGLFRVRUJ
control withdrawal may be the appropriate course of action, particularly
where the management of co-morbidities demands attention.
Managed withdrawal (detoxification) is a necessary step towards
drug-free treatment. The aims of early management of drug
detoxification are safe cessation or dose reduction, management of
symptoms and medical complications and retention of the patient in a
treatment program.
Most patients with opioid withdrawal can be managed in an
outpatient setting. Information and reassurance provided in a non-
judgemental way are vital to engage the patient in a realistic withdrawal
treatment program.
Admission to hospital may be required in the following
circumstances:
• Severe withdrawal syndrome (e.g. following administration of

antagonist)
• Significant complications (e.g. severe dehydration) 101
• Significant intercurrent illness (e.g. sepsis)
• Psychiatric co-morbidity.
TOXICOLOGY HANDBOOK
Pharmacological treatment of opioid withdrawal is categorised into
three types: opioid replacement therapy (e.g. methadone; buprenorphine),
antagonist detoxification (e.g. naltrexone) and symptomatic treatment.
Opioid replacement therapy

Methadone is used in opioid withdrawal and for maintenance in
abstinence programs. Methadone maintenance treatment achieves
significant reduction in heroin use and reduces mortality from heroin
overdose but does not produce an overall reduction in mortality when
compared with drug-free maintenance.
To commence methadone, patients should be referred for evaluation
and ongoing management by a specialist drug and alcohol service.
Methadone doses typically start at 20–40 mg/day and are tapered over
many weeks (e.g. by 3–5% each week).
Buprenorphine is a high-affinity partial µ-opioid agonist used as an
alternative to methadone. Doses start at 2–16 mg/day and are tapered
over many weeks. Buprenorphine treatment is as effective as methadone
in maintenance treatment of heroin dependence but less effective in
achieving treatment retention, particularly with low-dose or flexible-dose
regimens.
Detoxification
Rapid detoxification using naltrexone, buprenorphine and clonidine in
various combinations, or by rapid tapering of methadone, has been
successful in selected patients. Efficacy depends on patient selection and
ERRNVPHGLFRVRUJ
TABLE 2.14.1 Symptomatic treatment of opioid withdrawal
Dehydration
Fluid resuscitation
Nausea and vomiting
Metoclopramide 10 mg or prochlorperazine 5 mg or ondansetron 4 mg
PO, 6 hourly as required

Abdominal cramps and diarrhoea
Hyoscine 20 mg PO every 6 hours or atropine–diphenoxylate
(25 mcg–2.5 mg) two tablets PO every 6–8 hours
Myalgia and arthralgia
Paracetamol (1 g every 4 hours, not exceeding 4 g per day) or
ibuprofen (400 mg every 6 hours)
Anxiety, dysphoria and insomnia
Diazepam 5–10 mg PO every 6–8 hours for 2–3 days
Clonidine
Centrally acting alpha-2-adrenergic receptor agonist used to
attenuate the physical and psychological symptoms of opioid
withdrawal
102 Adverse effect is postural hypotension, especially in patients with
10
dehydration and bradycardia

2
Give a test dose of 75 micrograms PO, followed by lying and

standing blood pressure monitoring for 1 hour
TOXICOLOGY HANDBOOK
If symptomatic postural hypotension does not occur, commence 50

micrograms PO three times a day. The dose may be increased
if tolerated (e.g. up to 200–300 micrograms three times daily)
before tapering over the subsequent 5 days
close clinical supervision by a team experienced in specialised drug and

alcohol treatment. Ultra-rapid detoxification is an invasive procedure
involving the precipitation of severe opioid withdrawal using naltrexone,
often under general anaesthesia. This technique does not improve
abstinence rates and carries a high risk of serious adverse events
including death.
Supportive care
Patients should be reassured and assessed for potential co-morbidities
and complications. Fluid resuscitation for dehydration may be required.
The presence of altered mental status, fever or seizures prompts further
investigation for an alternative cause. Several medications are of value in
providing symptomatic relief (see Table 2.14.1).
Presentation with drug-related problems provides an opportunity for
patient counselling regarding the risks of drug abuse and dependence and
engagement in strategies to change behaviour.
References
Anonymous. Deaths and severe adverse events associated with anesthesia-assisted
rapid opioid detoxification – New York City, 2012. Morbidity and Mortality
Weekly Report 2013; 38:777–780.
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Mattick RP, Breen C, Kimber J, Davoli M. Methadone maintenance therapy versus no
opioid replacement therapy for opioid dependence. Cochrane Database of
Systematic Reviews 2009; 3:CD002209.
Mattick RP, Breen C, Kimber J, Davoli M et al. Buprenorphine maintenance versus
placebo or methadone maintenance for opioid dependence. Cochrane Database of
Systematic Reviews 2014; 2:C0002207.
Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of
North America 2000; 18(2):273–288.
Roxburgh A, Bruno R, Larance B, Burns L. Prescription of opioid analgesics and
related harms in Australia. Medical Journal of Australia 2011; 195:280–284.
Tetrault JM, O’Connor PG. Substance abuse and withdrawal in the critical care setting.
Critical Care Clinics 2008; 24:767–788.
2.15 SEDATIVE-HYPNOTIC USE DISORDER

Sedative-hypnotic use disorder is defined by DSM-V along the lines of 103
substance use disorder in general as outlined for alcohol (see Box 2.12.1).
Sedative-hypnotics include benzodiazepines, barbiturates, non-
benzodiazepine agents (zolpidem, zopiclone), baclofen, gamma-
TOXICOLOGY HANDBOOK
hydroxybutyrate, chloral hydrate and paraldehyde. Deliberate
self-poisoning with these agents is extremely common and the
management of these presentations together with the clinical toxicology
of the specific sedative-hypnotics is dealt with in Chapter 3.15: Baclofen,
Chapter 3.16: Barbiturates, Chapter 3.17: Benzodiazepines, Chapter 3.27:
Chloral hydrate and Chapter 3.37: Gamma-hydroxybutyrate (GHB).
SEDATIVE-HYPNOTIC WITHDRAWAL
Abrupt cessation or reduction in dose of a sedative-hypnotic agent can
produce a characteristic withdrawal syndrome in a dependent individual
not dissimilar to that of alcohol withdrawal. Withdrawal syndromes are
described for:
• Benzodiazepines
• Barbiturates
• Non-benzodiazepine sedative-hypnotic agents (zolpidem, zopiclone)
• Baclofen
• Gamma-hydroxybutyrate (GHB)
• Chloral hydrate
• Paraldehyde.
Pathophysiology
The sedative-hypnotic agents all modulate activity of the gamma-
aminobutyric acid (GABA) neurotransmitter complex. Abrupt withdrawal
leads to symptoms of GABA excess.
ERRNVPHGLFRVRUJ
Clinical features
There is a high degree of inter-individual difference in the rate of onset,
type and severity of withdrawal symptoms. Variability is determined
by dose and duration of therapy, rapidity of withdrawal, elimination
kinetics of the agent and patient factors. Onset of symptoms generally
occurs within 2–10 days of abrupt cessation, although withdrawal of

very-short-acting agents (e.g. GHB) or agents administered by the
intrathecal route (e.g. baclofen) may produce symptoms within hours.
The clinical presentation may reflect withdrawal from more than one
class of agent.
A severe and potentially lethal syndrome similar to delirium tremens
and including seizures occurs rarely. This is in contrast to opioid or
cannabis withdrawal, which does not cause delirium, autonomic
instability or seizures (see Chapter 2.14: Opioid use disorder and Chapter
3.23: Cannabinoids (marijuana)).
104
The commonly observed clinical features resemble those of alcohol
withdrawal (see Chapter 2.12: Alcohol use disorder), although
10
psychomotor and autonomic nervous system signs may be more

4
prominent:
TOXICOLOGY HANDBOOK
• Irritability and agitation

• Anorexia
• Inattention
• Memory disturbances
• Insomnia
• Palpitations
• Perceptual disturbances, including photophobia and hyperacusis
• Hallucinations
• Increased spasticity (baclofen).
Co-morbidities
Co-morbidities that should be considered in patients with sedative-
hypnotic withdrawal include:
• Alcohol withdrawal syndrome

• Dehydration
• Psychiatric morbidities.
Management
Where withdrawal develops as a result of an interruption in regular
benzodiazepine (or other sedative-hypnotic agent) use due to an
intercurrent medical illness, it is best to reverse the withdrawal syndrome
by reinstitution of the offending agent until the precipitating illness is
treated.
ERRNVPHGLFRVRUJ
Where the aim is to achieve permanent safe withdrawal or dose
reduction, alternative management strategies are adopted. The usual
strategy is to substitute a longer acting benzodiazepine for the agent
being ceased and then to slowly taper the dose. Tapering is titrated to
individual patient symptoms. If withdrawal symptoms increase, the dose
may be increased transiently or tapering attempted more slowly.
Typically, withdrawal takes weeks to complete with dosage decreases of
approximately 15% per week.
Management of severe sedative-hypnotic withdrawal with delirium or
seizures is similar to alcohol withdrawal syndrome (see Chapter 2.12:
Alcohol use disorder).
Several scores have been used to assess the severity of the
benzodiazepine withdrawal syndrome in order to guide admission
decisions and benzodiazepine dosing. However, most scores have not
been prospectively validated and should be used with caution.
Disposition 105
In most patients, sedative-hypnotic withdrawal is mild and management
in an outpatient setting is appropriate. Presentation with drug-related
TOXICOLOGY HANDBOOK
problems provides an opportunity for patient counselling regarding the
risks of drug abuse and dependence and engagement in strategies to
change behaviour.
Withdrawal in a residential setting, with supervision by specialised
staff with training in drug and alcohol issues, is appropriate in selected
circumstances:
• History of severe withdrawal

• Poor social support
• Failure of unsupervised outpatient withdrawal.
Inpatient sedative-hypnotic withdrawal is appropriate for a minority
of patients in whom there is a significant risk of delirium or seizures:
• Presentation in severe withdrawal

• Abnormal vital signs after initial treatment
• Hallucinations
• Altered conscious state
• Seizures
• Presence of medical complications or co-morbidities
• Presence of significant psychiatric co-morbidities.
References
Leo RJ, Baer D. Delirium associated with baclofen withdrawal: a review of common
presentations and management strategies. Psychosomatics 2005; 46:503–507.
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McDonough M, Kennedy N, Glasper A et al. Clinical features of gamma-
hydroxybutyrate (GHB) withdrawal: a review. Drug and Alcohol Dependence
2004; 75:3–9.
Olmedo R, Hoffman RS. Withdrawal syndromes. Emergency Medicine Clinics of
North America 2000; 18(2):273–288.
2.16 SOLVENT ABUSE

A solvent is defined as a liquid that has the ability to dissolve, suspend
or extract another material without chemical change to either the
material or solvent. Organic solvents are found in numerous household
and industrial products, including glues, household cleaners, degreasers,
thinners, paints, pharmaceuticals, cosmetics and pesticides. The group
includes aliphatic, cyclic, aromatic and halogenated hydrocarbons, ethers,
esters, glycols, ketones, aldehydes and amines (see Table 2.16.1).
Common solvents include isopropanol, toluene and xylene. Other
106 volatile hydrocarbons more commonly used as fuels, such as petrol,
10
kerosene and butane (used as lighter fuel), have similar physicochemical

6
properties, clinical effects and abuse potential.

TOXICOLOGY HANDBOOK
The recreational abuse of solvents involves inhalation of these

volatile substances for the purpose of achieving an alteration in mental
status, principally euphoria. Inhalational organic solvent abuse is a major
public health problem particularly afflicting adolescents and Indigenous
communities. The agent with the highest potential for abuse is toluene,
found primarily in glues, spray paints and lacquers.
PHYSICOCHEMICAL PROPERTIES
The organic solvents are all volatile liquids and well absorbed via the
inhalational route. Peak blood concentrations are achieved within
15–30 minutes of inhalation. These agents are highly lipid soluble and
following absorption are preferentially distributed to lipid-rich organs
notably the CNS and liver. After inhalation stops, excretion by the lungs
takes place. Solvents are also metabolised by the liver with elimination
half-lives in the order of 15–72 hours.
MECHANISM OF TOXICITY
While agents vary in their end-organ specificity, acute solvent toxicity
generally correlates with the volatility of an agent. They are lipophilic
and potent CNS depressants. High volatility is associated with a greater
risk of micro-aspiration and pneumonitis. Myelin toxicity is thought to
be the cause of the neuropsychiatric consequences associated with
long-term inhalational abuse and occupational exposure. Myocardial
sensitisation to catecholamines may be associated with cardiac
dysrhythmias and sudden death.
ERRNVPHGLFRVRUJ
TABLE 2.16.1 Chemicals used for inhalational abuse
Aliphatic hydrocarbons Nitrites

Acetylene Amyl nitrite
n-Butane Butyl nitrite
Cyclopropane Cyclohexyl nitrite
Isobutane Oxygenated compounds
n-Hexane Acetone
Propane Butanone
Aromatic hydrocarbons Diethyl ether
Toluene Dimethyl ether
Xylene Ethyl acetate
Mixed hydrocarbons Methyl acetate
Petrol Methyl isobutyl ketone
Kerosene Nitrous oxide
Halogenated hydrocarbons
Bromochlorodifluoromethane
Carbon tetrachloride
Chlorodifluoromethane
Chloroform 107
Dichlorodifluoromethane
Dichloromethane (methylene
chloride)
TOXICOLOGY HANDBOOK
1,2-Dichloropropane
Enflurane
Ethyl chloride
Halothane
Isoflurane
Methoxyflurane
Tetrachloroethylene
1,1,1-Trichloroethane
Trichloroethylene
Trichlorofluoromethane
Adapted from Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the
clinical toxicology of volatile substances. Drug Safety 1990; 5:359–383.
MODES OF ABUSE
Solvent abusers always employ the inhalational route with the following
methods described:
• ‘Huffing’: the liquid solvent is poured into a bag or piece of cloth

such as a sock and the liquid-soaked material is then held up to the
face as the abuser inhales deeply
• ‘Bagging’: the liquid is poured into a bag and the bag held over the
head
• ‘Sniffing’ or ‘snorting’: liquid is inhaled directly from the
container.
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CLINICAL FEATURES
The solvent abuser may present with acute solvent neurotoxicity or with
the CNS, metabolic, behavioural and social complications associated
with chronic abuse.
Acute inhalational exposure
Acute inhalation predominantly affects the CNS, causing altered

cognition that resembles ethanol intoxication. There is general
impairment of psychomotor function, as measured by reaction time,
manual dexterity, coordination and body balance. Patients are euphoric,
disinhibited, lethargic and ataxic with slurred speech and inappropriate
affect. More severe intoxication is characterised by confusion, depressed
level of consciousness, seizures and coma.
Inhalational exposure to solvents also causes intense irritation to the
mucous membranes of the eye, nose, throat and lower airways.
Inadvertent aspiration can induce chemical pneumonitis.
108
Sudden death, particularly associated with butane and propane, may
10
occur during acute exposure. Possible mechanisms are asphyxiation or

8
cardiac dysrhythmias induced by sensitisation of the myocardium to

TOXICOLOGY HANDBOOK
endogenous circulating catecholamines.

Chronic inhalational abuse
There is strong evidence to suggest that long-term toluene exposure
leads to persistent neurotoxicity characterised by structural and
functional brain abnormalities, as well as neuropsychological
impairment. Neuro-imaging studies suggest injury preferentially affects
white matter structures (lipid-rich myelinated structures), a pattern which
could be explained by the lipid-dependent distribution to myelinated
areas of the brain.
Persistent neurotoxicity is characterised by impaired cognition and
poor performance on most neuropsychological tests, including those
testing working memory and executive cognitive function. Although the
individuals engaging in chronic toluene abuse are likely to come from a
background of psychomotor, emotional and social deprivation, it does
appear that the abuse itself is associated with adverse effects in cognitive
and intellectual abilities. These effects further exacerbate the pre-existing
problems and complicate efforts to achieve detoxification, long-term
abstinence and rehabilitation.
It remains controversial as to whether long-term abstinence is
associated with significant improvement in neuropsychological function.
Chronic toluene abuse is also associated with a normal anion gap
metabolic acidosis largely due to distal renal tubular acidosis. Acidaemia,
hyperchloraemia and hypokalaemia may be profound (25% of chronic
abusers have serum K+ <2 mmol/L).
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MANAGEMENT
The solvent abuser who presents with acute solvent neurotoxicity
requires standard resuscitative measures for management of coma and
seizures. Behavioural disorders frequently necessitate early sedation with
titrated doses of intravenous benzodiazepine. Avoidance of secondary
complications such as hypoxia, hypoglycaemia and prolonged seizures
usually ensures survival.
Cardiac dysrhythmias, while a cause of early sudden death, are rarely
observed after arrival at hospital. Management along ACLS guidelines
with consideration of early use of beta-blocking agents for
tachydysrhythmias is appropriate.
Acid–base and electrolyte status should be checked early in the
patient suspected of chronic solvent abuse. Acidaemia may be prominent
even in a relatively asymptomatic patient. Patients may present with
life-threatening acidaemia requiring intensive care, sodium bicarbonate
replacement and management of profound hypokalaemia. 109
DISPOSITION
A period of observation lasting hours to days may be required until the
TOXICOLOGY HANDBOOK
acute CNS and metabolic disorders resolve. This may occur in the
emergency department or intensive care unit but continuous and adequate
supervision is essential to prevent injury to the patient and staff.
After resolution of acute toxicity, the issues associated with chronic
solvent abuse must be addressed. Management is challenging and as
much socio-political as medical or psychological. Achieving sustained
abstinence in the setting of ongoing social deprivation is difficult. Many
of the neuropsychiatric effects associated with chronic abuse are likely to
be irreversible and further complicate management.
SOLVENT WITHDRAWAL
Physical withdrawal from solvents is generally mild with lethargy,
headaches, anxiety or depressed mood. It may last from several days to a
few weeks and does not require any specific treatment.
SOLVENT ABUSE DURING PREGNANCY AND LACTATION

Most solvents, including toluene, are highly lipid soluble and so cross
the placenta easily. A fetal solvent syndrome similar to fetal alcohol
syndrome is described. Abstinence phenomenon similar to alcohol
withdrawal in the postpartum period is also described.
References
Carlisle EJF, Donnelly SM, Vasuvattakul S et al. Glue-sniffing and distal renal tubular
acidosis: sticking to the facts. Journal of the American Society of Nephrology
1991; 1:1019–1027.
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Dick FD. Solvent neurotoxicity. Occupational and Environmental Medicine 2006;
63:221–226.
Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the clinical toxicology
of volatile substances. Drug Safety 1990; 5:359–383.
hydrocarbon abuse: clinical toxicology teaching case from NAACT acute and
intensive care symposium. Clinical Toxicology 2014; 52:141–145.
Maruff P, Burns CB, Tyler P et al. Neurological and cognitive abnormalities associated
with chronic petrol sniffing. Brain 1998; 121:1903–1917.
Rosenberg NL, Grigsby J, Driesbach J et al. Neuropsychological impairment and MRI
abnormalities associated with chronic solvent abuse. Clinical Toxicology 2002;
40(1):21–24.
Yucel M, Takagi M, Walterfang M et al. Toluene misuse and long-term harms:
a systematic review of the neuropsychological and neuroimaging literature.
Neuroscience and Biobehavioural Reviews 2008; 32:910–926.
2.17 BODY PACKERS AND STUFFERS

110 ‘Body packing’ refers to the internal concealment of illicit drugs (usually
in large quantities) for transportation across international borders. The
11
0
drug is usually of a single type and meticulously packaged in plastic,

TOXICOLOGY HANDBOOK
latex, condoms or balloons. Many hours have usually elapsed before

presentation to the emergency department, so most packets have already
entered the small or large intestine. The vagina and rectum are not
usually used for body packing, as they are more likely to be discovered
on physical examination. Cocaine, heroin, amphetamine,
3-4-methylenedioxymethamphetamine (MDMA, ‘ecstasy’), cannabis and
hashish have all been reported to have been transported by body packing.
Up to 1 kg of drug, divided into more than 100 packets, may be
transported by a single individual. Body packers (often referred to as
‘mules’ or ‘swallowers’) use constipating agents such as atropine-
diphenoxylate to slow gastrointestinal transit such that it may take from
days to weeks for all packages to pass.
‘Body stuffing’ refers to the hasty internal concealment of illicit
drugs immediately prior to apprehension by authorities. The packages
are more likely to contain multiple different drugs, are usually prepared
in a rushed manner and much more likely to leak. They may consist
simply of a small plastic bag or foil pouch. The delay from ingestion to
presentation to the emergency department is much shorter and the
ingested packets are frequently still within the stomach. The vagina and
rectum are alternative sites for drug concealment in ‘body stuffing’.
The management of body packers and body stuffers poses multiple
challenges:
• Many times the lethal dose of illicit drug may have been ingested.
• Patients may not provide an accurate history, making risk assessment
problematic.
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• The treating clinician may be directed by law enforcement officers to
conduct procedures for which the patient has not consented.
• There are few prospective studies to guide management.
CLINICAL PRESENTATION
Body packers present in three settings:
• Acute drug intoxication or fear of impending rupture and
intoxication
• Request by authorities for medical assessment following arrest
• Development of surgical complications, usually bowel obstruction
but bowel perforation, oesophageal obstruction and oesophageal
rupture are also reported.
MANAGEMENT OF ‘BODY STUFFERS’

Patients are initially observed in a monitored environment with
intravenous access. If the patient presents within 1 hour and is 111
cooperative, a single dose of 50 g oral activated charcoal is indicated.
All orifices should be examined. Non-contrast abdominal CT scan is
TOXICOLOGY HANDBOOK
useful to localise or exclude the presence of packets. Urine toxicology
screens for drugs of abuse rarely alter clinical management. Patients who
are asymptomatic and have no packets detected on examination or
abdominal CT scan may be safely discharged. Patients with clinical
features of intoxication are treated accordingly.
MANAGEMENT OF ‘BODY PACKERS’

Body packers are given high triage priority and are initially managed in
an area equipped for cardiopulmonary monitoring and resuscitation.
Immediate resuscitation priorities are attended to as outlined in Chapter
1.2: Resuscitation. These include administration of supplemental oxygen,
obtaining intravenous access and commencement of continuous cardiac
monitoring.
Risk assessment
Body packers transport many times the lethal dose of cocaine, heroin or
amphetamines. The onset of signs of drug intoxication may herald
imminent catastrophic deterioration.
It is important to obtain a detailed history from the patient, if
possible. The type of drug, number and construction of packages and
time of ingestion are vital components of the history. In those patients
admitting (or proven) to have swallowed drug packets, there is good
correlation between the number of packets self-reported and the total
number of packets retrieved. The physical examination should look for
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any evidence of drug intoxication and surgical complications (e.g. bowel
obstruction).
Supportive care and disposition

The patient should be admitted to a clinical area equipped and staffed to
observe for, and manage, the rapid onset of drug intoxication. In most
settings this will be an intensive care unit or emergency observation

ward. Staff are briefed on the potential symptoms of intoxication that
will prompt urgent review and aggressive therapy. Senior medical staff
must be available 24 hours a day. Intravenous access is maintained until
discharge. Continuous ECG and pulse oximetry monitoring are kept in
place when the patient is not ambulating, and especially when asleep.
Asymptomatic patients may eat a normal diet. Ambulation around the
ward is encouraged, as bed rest appears to be a risk factor for bowel
obstruction. Patients are observed until the expected numbers of packets
and/or three package-free stools are passed and repeat abdominal CT
112 scanning is negative. The mean time to pass all packages is
11
approximately 5 days.
2
TOXICOLOGY HANDBOOK
Investigations
Urine toxicology screening has been advocated but has low sensitivity.
A positive test suggests the need for further investigation and observation
but a negative test does not exclude body packing or indicate that the
patient is safe for discharge.
Non-contrast abdominal CT scanning is the most sensitive
investigation used to detect internal drug concealment and is now the
investigation of choice. The sensitivity, specificity, positive predictive
value and negative predictive value approach 100% for CT scanning of
patients suspected of concealing drugs. Packet counts on CT are accurate
when <15 packets exist. However for higher numbers of packets,
correlation between packets counted on CT and total number passed is
poor. Once all expected packets are passed, repeat abdominal CT scan is
performed to confirm passage of all packets.
Decontamination
Cooperative asymptomatic patients may be administered 50 g activated
charcoal, in case of package leakage or rupture.
Asymptomatic patients, even those transporting cocaine, may be
treated conservatively and observed until all packages are retrieved.
The incidence of serious complications such as late-onset drug
intoxication, bowel obstruction, urgent laparotomy or death is less
than 5% with conservative management. A light or liquid diet plus
gentle laxatives are often ordered in an effort to speed passage of
packages.
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The role of more aggressive decontamination using whole bowel
irrigation is controversial. It is not indicated for heroin body packers
where a good outcome in the event of package rupture can be assured
with supportive care and antidote administration.
Endoscopy may be considered to retrieve packages from the stomach
that are too large to pass the pylorus. Colonoscopy may be considered to
retrieve packages retained in either of the colonic flexures. These
procedures carry a risk of package rupture.
Patients with cocaine body packing who show signs of significant
intoxication should be resuscitated and managed supportively pending
urgent transfer to theatre for laparotomy, enterotomy and careful removal
of packages. Similarly, patients who develop signs of bowel obstruction
or perforation should have their packages surgically removed.
Antidotes
Naloxone is an adjunct to the management of opioid intoxication. In
body packers, large initial doses may be required (e.g. 2–10 mg) 113
followed by an intravenous infusion (see Chapter 4.18: Naloxone). The
management of cocaine and amphetamine intoxication is described in
TOXICOLOGY HANDBOOK
Chapter 3.30: Cocaine and Chapter 3.8: Amphetamines and other
sympathomimetics.
References
Asha SE, Higham M, Child P. Sensitivity and specificity of CT scanning for
determining the number of internally concealed packages in “body-packers”.
Emergency Medicine Journal 2014 Feb 19. doi: 10.1136.
Beckley I, Ansari NA, Khwaja HA et al. Clinical management of cocaine body
packers: the Hillingdon experience. Canadian Journal of Surgery 2009:
52(5):417–421.
Das D, Ali B, Mackway-Jones K. Conservative management of asymptomatic cocaine
body packers. Emergency Medicine Journal 2003; 20:172–174.
De Bakker JK, Nanayakkara PWB, Geeraedts LMG et al. Body packers: a plea for
conservative management. Langenbecks Archives of Surgery 2012; 397:125–130.
Hergan K, Kofler K, Oser W. Drug smuggling by body packing: what radiologists
should know about it. European Radiology 2004; 14(4):736–742.
Traub SJ, Hoffman RS, Nelson LS. Body packing – the internal concealment of illicit
drugs. New England Journal of Medicine 2003; 349:2519–2526.
2.18 OSMOLAR GAP

The osmolar gap is a calculated value that assists in the diagnosis of
toxic alcohol poisoning. It is particularly useful when laboratory
estimation of serum methanol and ethylene glycol levels are not readily
available.
Osmolality (see Table 2.18.1) of a solution is measured by an
osmometer in a laboratory, usually by freezing point depression.
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TABLE 2.18.1 Definitions
Osmole: the amount of a substance that yields, in ideal solution, that

number of particles that would depress the freezing point of the solvent
by 1.86°K
Osmolality: the number of osmoles of solute per kilogram of solvent
Osmolarity: the number of osmoles of solute per litre of solution
Osmolarity of a solution is calculated from a formula that represents

the solutes, which under ordinary circumstances contribute nearly all of
the osmolality of the sample. The most widely used formula is:
Osmolarity (mOsmol L ) = 2 × [sodium mmol L ]
+ [urea mmol L ] + [glucose mmol L ]
In clinical toxicology, ethanol is so ubiquitous that it is routinely

114 included in the calculation:
11
4
Osmolarity (mOsmol L ) = 2 × [sodium mmol L ] + [urea mmol L ]

+ [glucose mmol L ] + [ethanol mmol L ]
TOXICOLOGY HANDBOOK
Osmolar gap is the difference between the osmolality (as measured

in the laboratory) and the osmolarity as calculated from measured solute
concentrations.
Osmolar gap = Measured osmolality − Calculated osmolarity
Notes:
1 All solute concentrations must be in mmol/L (SI units). If ethanol is
reported in non-SI units, it is converted to mmol/L as follows:
ethanol mg/dL/4.6 or ethanol % × 218.
2 The units of osmolality and osmolarity are different so the osmolar
gap is expressed as a number without units.
A normal osmolar gap is <10. A small gap exists because the
calculation does not take into account osmotic activity generated by
chloride, potassium, sulfate, phosphate, calcium, magnesium, lactate,
ammonia, serum proteins and lipids.
To safely interpret an elevated osmolar gap, the following principles
apply:
• An elevated osmolar gap suggests the presence of high

concentrations of unmeasured (and potentially toxic) osmotically
active compounds (see Table 2.18.2).
• A number of non-toxicological conditions also cause an elevated
osmolar gap (see Table 2.18.3).
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TABLE 2.18.2 Exogenous agents associated with elevated osmolar gap
Acetone
Ethanol
Ethylene glycol
Glycerol
Glycine
Isopropyl alcohol
Mannitol
Methanol
Propylene glycol (diluent in several medications e.g. diazepam, phenytoin)
Adapted from Dart RC, ed. Medical Toxicology. 3rd edn (text). Philadelphia: Lippincott
Williams & Wilkins; 2004.
TABLE 2.18.3 Non-toxicological conditions associated with elevated

osmolar gap
Alcoholic ketoacidosis 115

Chronic renal failure
Diabetic ketoacidosis
TOXICOLOGY HANDBOOK
Hyperlipidaemia
Hyperproteinaemia
Massive hypermagnesaemia
Severe lactic acidosis
Shock
Trauma and burns
Adapted from Dart RC, ed. Medical Toxicology. 3rd edn (text). Philadelphia: Lippincott
Williams & Wilkins; 2004.
• In suspected toxic alcohol ingestion (due to history of ingestion or

presence of anion gap metabolic acidosis), an elevated osmolar gap
supports the diagnosis.
— In confirmed significant toxic alcohol ingestion the osmolar gap
is frequently very elevated (>50).
• A normal osmolar gap does not exclude potentially life-threatening
toxic alcohol ingestion for the following reasons:
— Small concentrations of toxic alcohols not detected by this
surrogate measure may still cause significant intoxication
— Late in the clinical course, the parent compounds (alcohols) are
already metabolised to non-osmotically active compounds.
The serum concentration of a particular alcohol suspected to be
present can be estimated from the osmolar gap. Multiply the osmolar gap
by the conversion factors (the molecular weight of the alcohol divided
by 10) listed in Table 2.18.4 to estimate the alcohol concentration in
conventional units (mg/dL).
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TABLE 2.18.4 Estimated alcohol levels based on osmolar gap
To calculate the serum alcohol level in mg/dL multiply the osmolar gap by
the conversion factor
Alcohol Conversion factor

Ethanol 4.6
Ethylene glycol 6.2
Isopropyl alcohol 6.0
Methanol 3.2
Propylene glycol 7.2
Adapted from Olsen KR. Poisoning and Drug Overdose. 2nd edn. Norwalk, CT:
Appleton and Lange; 1994.
References
Koga Y, Purssell RA, Lynd LD. The irrationality of the present use of the osmole gap:
116 applicable physical chemistry principles and recommendations to improve the
11
validity of current practices. Toxicological Reviews 2004; 23(3):203–211.

6
Krasowski MD. A retrospective analysis of glycol and toxic alcohol ingestion: utility
of anion and osmolal gaps. BMC Clinical Pathology 2012; 12:1.
TOXICOLOGY HANDBOOK
Purssell RA, Lynd LD, Koga Y. The use of the osmole gap as a screening test for the
presence of exogenous substances. Toxicological Reviews 2004; 23(3):189–202.
2.19 ACID–BASE DISORDERS

The assessment of acid–base abnormalities is a core competency in
critical care and clinical toxicology. These disorders are manifestations
of underlying disease processes and not diagnoses in themselves.
Several potentially lethal poisonings produce characteristic acid–base
abnormalities. The detection of any acid–base disorder during assessment
of the poisoned or potentially poisoned patient mandates careful
characterisation to produce a differential diagnosis as the initial step to
definitive diagnosis and management.
Assessment and characterisation of an acid–base disturbance requires
information derived from the history, physical examination and basic
investigations including electrolytes, creatinine, blood glucose and
arterial blood gases.
In the history and physical examination, particular attention is paid to:
• Past medical history

— Diabetes
— Renal failure
• Current medications
— Metformin
— Salicylates
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• Potential chemical or pharmaceutical ingestions
• Diarrhoea or vomiting
• Level of consciousness
• Respiratory rate
• Hydration and urine output.
This information can be evaluated in a systematic fashion using the
five-step approach proposed by Whittier and Rutecki:
Step 1: Determine primary acid–base disturbance by assessing pH.

Acidaemia exists if pH <7.36.
Alkalaemia exists if pH >7.44.
Note: The body always compensates for an acid–base disturbance but
this compensation is never complete (the pH cannot return to
normal). Therefore, if a single acid–base disturbance exists, the
primary process can be identified by the serum pH. If there is
significant abnormality of HCO3− and PaCO2 with normal pH, there
117
must be at least two counteracting pathologies.
Step 2: Determine whether the primary process is respiratory,
TOXICOLOGY HANDBOOK
metabolic or both by assessing PaCO2 and HCO3−.
Respiratory acidosis exists if PaCO2 >44 mmHg.
Respiratory alkalosis exists if PaCO2 <40 mmHg.
Metabolic acidosis exists if HCO3− <25 mmol/L.
Metabolic alkalosis exists if HCO3− >25 mmol/L.
Step 3: Calculate the anion gap.

The anion gap represents the concentration of all unmeasured anions
in the plasma. It is calculated from the following formula:
Anion gap = Na + − (Cl− + HCO3 − )
Notes:
1 The normal anion gap ranges from 8 to 16 mmol/L.
2 Addition of K+ to the anion gap calculation is not required.
3 Correct for hypoalbuminaemia (albumin is an anion) if
present. For every 10 g/L below normal, add 2.5 to the
anion gap.
4 Acid anions produced during a metabolic acidosis are not
measured as part of the usual laboratory biochemical profile.
The H+ ions produced are buffered by HCO3− leading to a
reduction in measured anions (HCO3−) to accompany the
increase in unmeasured acid anions, and so the calculated
anion gap increases.
5 Minor degrees of acidosis and elevation of anion gap are
common in clinical practice. An idiopathic minor abnormality
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prompts supportive care and re-evaluation in 4 hours. In most
cases the abnormality will be improving.
An anion gap that is rising or >20 at any time prompts immediate
investigation (see Table 2.19.1). Two-thirds of patients with an anion
TABLE 2.19.1 Causes of anion-gap acidosis (mnemonic ‘CAT

MUDPILES’)
C Carbon monoxide, cyanide

A Alcohol, alcoholic ketoacidosis
T Toluene
M Metformin, methanol
U Uraemia
D Diabetic ketoacidosis
P Paracetamol, propylene glycol, paraldehyde
I Iron, isoniazid (INH)
L Lactic acidosis (numerous causes)
E Ethylene glycol
118 S Salicylates, starvation ketoacidosis
11
8
TABLE 2.19.2 Causes of a low anion gap (<6)

TOXICOLOGY HANDBOOK
Increased unmeasured cations Artefactual hyperchloraemia

Hypercalcaemia Bromism
Hypermagnesaemia Iodism
Lithium intoxication Hypertriglyceridaemia
Multiple myeloma and other
‘gammopathies’
Decreased unmeasured anions
Dilution
Hypoalbuminaemia
TABLE 2.19.3 Causes of non-anion-gap metabolic acidosis
Abnormal bicarbonate loss or Mnemonic ‘USED CARP’

chloride retention
Drugs U Ureterostomy
Acetazolamide (+ others with S Small bowel fistula
carbonic anhydrase activity, E Extra Cl−
e.g. topiramate) D Diarrhoea
Acidifying agents (e.g. C Carbonic anhydrase inhibitors
ammonium chloride) A Adrenal insufficiency
Cholestyramine R Renal tubular acidosis
Gastrointestinal bicarbonate loss P Pancreatic fistula
Diarrhoea
Pancreatic fistula
Rapid hydration with normal
saline (increased chloride)
Renal bicarbonate loss
Renal tubular acidosis
Uretoenterostomy
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TABLE 2.19.4 Causes of metabolic alkalosis
Administration of bases Urinary acid loss

Antacids Adrenogenital syndrome
Dialysis Bartter’s syndrome
Milk–alkali syndrome Cushing’s syndrome
Gastrointestinal acid loss Diuretics
Protracted vomiting or Licorice (glycyrrhizic acid)
nasogastric suction Primary hyperaldosteronism
(chloride loss) Volume contraction
Renal bicarbonate retention
Chronic hypercapnia
Hypochloraemia
Hypokalaemia
TABLE 2.19.5 Causes of respiratory acidosis
Acute Chronic
119
Airway obstruction Kyphoscoliosis
Aspiration Lung diseases
Bronchospasm Neuromuscular disorders
TOXICOLOGY HANDBOOK
Drug-induced CNS depression Obesity
Hypoventilation of CNS or muscular
origin
Pulmonary disease
TABLE 2.19.6 Causes of respiratory alkalosis
CNS-mediated hyperventilation Pulmonary

Increased intracranial pressure Congestive cardiac failure
Cerebrovascular accidents Mechanical hyperventilation
Psychogenic Pneumonia
Hypoxia-mediated hyperventilation Pulmonary emboli
Altitude Sepsis
Anaemia Toxin-induced hyperventilation
V/Q mismatch Nicotine
Salicylate
Xanthines
gap in the range of 20–29 mmol/L will be found to have a metabolic

acidosis. If the anion gap is >30, metabolic acidosis is invariably
present.
Step 4: Assess the degree of compensation.
Metabolic acidosis: expected PaCO2 in mmHg is 1.5 × HCO3− + 8
(range: ± 2).
Metabolic alkalosis: expected PaCO2 in mmHg is 0.7 × HCO3− + 20
(range: ± 2).
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TABLE 2.19.7 Causes of hyperlactataemia
Type A: Imbalance between

oxygen demand and supply Type B: Metabolic derangements
Carbon monoxide poisoning Beta-2-agonists

Cyanide Cancer
Excessive oxygen demand-seizure, Ethanol (increased hepatic NADH

hyperpyrexia, shivering, exercise and decreased conversion of
Shock lactate to pyruvate)
Severe anaemia Hepatic failure
Severe hypoxia Inborn errors of metabolism
Psychogenic hyperventilation Ketoacidosis
Metformin
Sepsis
Vitamin deficiency (thiamine, biotin)
TABLE 2.19.8 Interpretation of delta ratio

120
Delta ratio Interpretation
12
0
<0.4 Hyperchloraemic normal anion gap acidosis

TOXICOLOGY HANDBOOK
0.4–0.8 Consider combined high anion gap and low anion gap
acidosis but ratio of <1 is also associated with renal failure
1–2 Usual for high anion gap acidosis

Average value for lactic acidosis is 1.6
Diabetic ketoacidosis usually close to 1 due to ketone loss
>2 Pre-existing elevated HCO3− likely – consider concurrent

metabolic acidosis or pre-existing compensated
respiratory acidosis
Source: http://www.anaesthesiamcq.com/AcidBaseBook
Respiratory acidosis: HCO3− should increase by 1 mmol/L (acute)

or 4 mmol/L (chronic) for every 10 mmHg increase in PaCO2.
Respiratory alkalosis: HCO3− should decrease by 2 mmol/L (acute)
or 5 mmol/L (chronic) for every 10 mmHg decrease in PaCO2.
Step 5: Determine if there is a 1 : 1 relationship between anions in
the blood (delta ratio).
Assuming all buffering in metabolic acidosis is by HCO3−, the
increase in the anion gap should be equal to the decrease in HCO3−
concentration and the ratio between these two changes (‘delta ratio’)
should be equal to one.
The delta ratio can be useful in the assessment of metabolic acid–
base disorders (see Table 2.19.8), but one should always be wary of
over-interpretation and always look for other evidence to support the
diagnosis.
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References
Gabow PA, Kaehny WD, Fennessey PV et al. Diagnostic importance of an
increased serum anion gap. New England Journal of Medicine 1980;
303(15):854–858.
Brandis K. Acid–base physiology. Available at: http://www.anaesthesiamcq.com/
AcidBaseBook [accessed 16 September 2014].
Whittier WL, Rutecki GW. Primer on clinical acid–base problem solving. Disease
Monitoring 2004; 50:117–162.
2.20 THE 12-LEAD ECG IN TOXICOLOGY

The 12-lead ECG is a non-invasive, inexpensive and readily available
tool that identifies occult but potentially lethal cardiac conduction
abnormalities, such as those seen in tricyclic antidepressant
cardiotoxicity. For these reasons, it is recommended as a screening test
in all patients who present following deliberate self-poisoning. The 121
12-lead ECG provides valuable real-time prognostic information that
reflects toxic effects at the target organ, often not available from
TOXICOLOGY HANDBOOK
clinical evaluation or serum drug assays. Serial ECGs allow
monitoring of the progression or regression of cardiotoxicity during
the clinical course. They inform decision making with regard to the
level of care and monitoring required, and appropriate disposition
planning.
ELECTROPATHOPHYSIOLOGY
The changes in rate, rhythm and intervals detected on the 12-lead ECG
in acute poisoning reflect a variety of toxic effects on the cardiac
conducting system (see Figure 2.20.1). Normal intervals are shown in
Figure 2.20.2. Pathophysiological mechanisms include:
Fast sodium channel blockade (agents listed in Table 2.20.1)

• Slowed sodium influx during phase 0 of the cardiac action potential
manifesting as:
— Widened QRS
— Right axis deviation of the terminal QRS (see
Figure 2.20.3).
— Bradycardia (although tachycardia secondary to other factors is
more commonly observed)
— Ventricular tachycardia and ventricular fibrillation
Blockade of potassium efflux during cardiac repolarisation (agents
listed in Table 2.20.2)
• Prolongation of the QT interval
• Torsades de pointes
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FIGURE 2.20.1 The myocardial action potential and corresponding
ECG trace
2
Measured Potential (mV)
0 3
Action potential
Na+ channel blocker toxicity

+
K efflux blocker toxicity
122 ECG
12
Time (ms)
2
TOXICOLOGY HANDBOOK
Diagram from Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poisoned
patient. Emergency Medicine Clinics of North America 2006; 24(1):159–177.
FIGURE 2.20.2 Normal ECG parameters

Rate 60–100/minute
PR interval: <200 ms (5 small squares)
QRS duration: <100 ms (2.5 small squares)
QTC interval: <450 ms
QTc = QT/√ R–R
T
P
Q
S
PR
QRS
QT
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TABLE 2.20.1 Agents associated with fast sodium channel blockade
(QRS widening)
Tricyclic antidepressants Local anaesthetics

Amitriptyline Bupivacaine
Desimipramine Cocaine
Dothiepin Ropivacaine
Imipramine Phenothiazines
Nortriptyline Thioridazine
Class 1A antidysrhythmic agents Amantadine
Disopyramide Carbamazepine
Procainamide Chloroquine
Quinidine Diltiazem
Class 1C antidysrhythmic agents Diphenhydramine
Flecainide Hydroxychloroquine/chloroquine
Propoxyphene/dextropropoxyphene
Propranolol
Quinine
123
FIGURE 2.20.3 ECG changes in tricyclic antidepressant (or other fast
TOXICOLOGY HANDBOOK
Na channel blocker) toxicity
Features consistent with fast sodium channel blockade:
● QRS >100 ms in lead II
● Right axis deviation of terminal QRS
— Terminal R wave >3 mm in aVR
— R/S ratio >0.7 in aVR
Dominant R wave in aVR
Widening of the QRS
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TABLE 2.20.2 Agents associated with blockade of potassium efflux
(QT prolongation)
Antipsychotic agents Other antidepressants

Amisulpride Bupropion
Chlorpromazine Citalopram
Droperidol Escitalopram
Haloperidol Mianserin
Olanzapine Moclobemide
Quetiapine Antihistamines
Thioridazine Diphenhydramine
Ziprasidone Doxylamine
Class 1A antidysrhythmic agents Loratadine
Quinidine Promethazine
Disopyramide Terfenadine
Procainamide Chloroquine
Class 1C antidysrhythmic agents Hydroxychloroquine
Flecainide Quinine
Class III antidysrhythmic agents Fluoroquinolones
124 Sotalol Moxifloxacin
12
Tricyclic antidepressants Macrolides

4
Amitriptyline Azithromycin
Desimipramine Erythromycin
TOXICOLOGY HANDBOOK
Doxepin Methadone
Imipramine
Nortriptyline
Na+–K+-ATPase pump blockade (cardiac glycosides)

• Increased automaticity
• Decreased AV node conduction
— 1st degree heart block (prolonged PR interval)
— 2nd degree heart block
— 3rd degree (complete) heart block
Calcium channel blockade
• Sinus bradycardia
• Intraventricular conduction defects
Beta-adrenergic receptor blockade
• Bradycardia
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Myocardial ischaemia
• ST-segment depression or elevation
• Conduction abnormalities
Hyperkalaemia
• Peaked T waves
•
Conduction abnormalities
Hypocalcaemia, hypomagnesaemia, hypokalaemia
• QT prolongation.
TRICYCLIC ANTIDEPRESSANTS
A QRS duration >100 ms suggests blockade of cardiac fast sodium
channels. In combination with right axis deviation of the terminal QRS,
it is virtually pathognomonic (see Figure 2.20.3). Most studies examine
ECG changes in TCA intoxication and are small or retrospective.
However, the following appear to be associated with major toxicity: 125
• QRS >100 ms (2.5 small squares) is associated with seizures
• QRS >160 ms (4 small squares) is associated with ventricular
TOXICOLOGY HANDBOOK
dysrhythmias
• Right axis deviation of the terminal QRS as defined by
— Terminal R wave >3 mm in aVR
— R/S ratio >0.7 in aVR.
SYSTEMATIC ANALYSIS OF THE 12-LEAD ECG OF

A POISONED PATIENT
1 Determine rate and rhythm.
2 Determine PR interval – is there any degree of heart block?
3 Determine QRS duration in lead II. The studies examining QRS
duration in tricyclic antidepressant intoxication use manual
measurements to measure QRS in limb lead II. This may not
correspond with the QRS as calculated by an automated ECG
machine using complex algorithms. It is best to check the interval
manually in lead II.
4 Check for right axis deviation of the QRS. A large terminal R wave
in aVR or increased R/S ratio indicates slow rightward conduction
and is characteristic of fast sodium channel blockade. If not
pathological, it remains static in appearance and severity throughout
the course of the poisoning. Comparison with pre-poisoning ECGs is
useful.
5 Determine QT interval. A prolonged QT interval predisposes to the
development of torsades de pointes, a polymorphic ventricular
tachycardia. Torsades de pointes is potentially fatal because of its
propensity to degenerate into ventricular fibrillation. Torsades de
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FIGURE 2.20.4 QT interval nomogram for determining ‘at risk’ QT-HR
pairs from a single 12-lead ECG
QT interval
(ms)
20 40 60 80 100 120 140 160
Heart rate (bpm)
The mean QT interval as measured manually on multiple leads of a 12-lead ECG is

plotted against the heart rate (HR) measured on the ECG. If the point is above the
line, the QT-HR is regarded ‘at risk’ for the development of torsades de pointes.
Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and
torsades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine
126 2007:100:609–615.
12
6
TOXICOLOGY HANDBOOK
pointes is more likely to occur where there is coexisting bradycardia.

The dysrhythmogenic risk for drug-induced QT prolongation is
accurately predicted by the ‘QT nomogram’, which plots QT versus
heart rate (see Figure 2.20.4), and is more reliable than derived
calculations such as the QTc.
6 Check for evidence of increased cardiac ectopy or automaticity.
7 Check for evidence of hyperkalaemia.
8 Check for evidence of myocardial ischaemia.
References
Boehnert MT, Lovejoy FH. Value of the QRS duration verus the serum drug level
in predicting seizures and ventricular arrhythmias after an acute overdose of
tricyclic antidepressants. New England Journal of Medicine 1985; 313:474–479.
Chan A, Isbister GK, Kirkpatrick CMJ et al. Drug-induced QT prolongation and
torsades de pointes: evaluation of a QT nomogram. Quarterly Journal of Medicine
2007; 100:609–615.
Holstege CP, Eldridge DL, Rowden AK. ECG manifestations: the poisoned patient.
Emergency Medicine Clinics of North America 2006; 24(1):159–177.
Liebelt EL, Francis D, Woolf AD. ECG lead AVR versus QRS interval in predicting
seizures and arrhythmias in acute tricyclic antidepressant toxicity. Annals of
Emergency Medicine 1995; 26:195–201.
Niemann JT, Bessen HA, Rothstein RJ et al. Electrocardiographic criteria for tricyclic
antidepressant cardiotoxicity. American Journal of Cardiology 1986;
57:1154–1159.
Wolfe TR, Caravati EM, Rollins DE. Terminal 40-ms frontal plane QRS axis as a
marker for tricyclic antidepressant overdose. Annals of Emergency Medicine
1989; 18:348–351.
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2.21 POISONING DURING PREGNANCY
AND LACTATION
Management decisions regarding poisoning or envenoming in the
pregnant or lactating patient take into consideration the risks to the fetus
or infant of the poisoning or its treatment.
Pregnancy-induced physiological changes affect drug
pharmacokinetics and pharmacodynamics in the following ways:
1 Absorption – delayed gastric emptying and intestinal transit time
slow drug absorption and may prolong the period where
decontamination is of potential benefit
2 Distribution – increased blood volume (45–50%) increases volume of
distribution and potentially decreases plasma levels; dilution of
plasma proteins increases free drug levels
3 Elimination – hepatic enzyme systems are altered by circulating
127
hormones; renal blood flow and glomerular filtration rate increase.
Most drugs cross the placenta by diffusion and maternal blood levels
TOXICOLOGY HANDBOOK
are the most significant determinant of fetal exposure. Maternal blood
levels are usually greater than those of the fetus, although for some
agents they are the same and for others fetal levels exceed maternal
levels (e.g. valproic acid and diazepam).
On a practical level, acute management of overdose in the pregnant
patient rarely differs from that of the non-pregnant patient. In particular,
paracetamol and iron overdose, which are relatively common in this
group, are managed along standard lines.
Excellence in supportive care of the poisoned mother ensures the
best physiological conditions to minimise fetal compromise. Early
detection and correction of hypoxia, hypotension, hypoglycaemia and
seizures in the mother ensure the best outcome for the fetus. Fetal
monitoring may be useful in detecting fetal compromise and the
response to treatment.
Greater circulating volumes, increased respiratory rate and
physiological resting tachycardia in the pregnant patient disguise
hypovolaemia and respiratory compromise until later stages.
Oral activated charcoal and whole bowel irrigation do not pose any
special risks to pregnant patients and these forms of decontamination are
implemented whenever indicated as for non-pregnant patients.
Poisoning with a limited number of agents poses a potentially greater
risk to the fetus than the mother and the threshold for treatment is
lowered. These include:
• Carbon monoxide
• Methaemoglobin-inducing agents
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• Lead
• Salicylates.
Consideration of the need to emergently deliver near-term infants in
poisoned mothers is a complicated issue that should be managed with
toxicology and obstetric expertise.
In general, if the fetus survives a maternal intentional ingestion, the

risk of teratogenicity is low. The teratogenic risk is theoretically greater
when the exposure occurs during the first trimester. It is important that
the pregnant patient be counselled regarding these risks once she has
recovered. Assistance in providing such advice can be obtained by
contacting the drug information services at tertiary women’s hospitals.
Australian drug risk classifications for pregnancy are available for all
therapeutic agents. Paracetamol overdose treated with N-acetylcysteine
does not appear to be associated with fetal abnormality even when the
exposure occurs during the first trimester.
128 The decision to continue breastfeeding during acute poisoning
involves a risk–benefit analysis. Most drugs are excreted in breast milk.
12
8
The percentage of maternal dose likely to be received by an infant is

very low (<2–3%) and usually does not pose a poisoning risk.
TOXICOLOGY HANDBOOK
Nonetheless, it is usually best to interrupt breastfeeding until the mother

recovers, provided this can be done without compromising infant
nutrition.
References
Anderson GD. Pregnancy-induced changes in pharmacokinetics: a mechanistic-based
approach. Clinical Pharmacokinetics 2005; 44(10):989–1008.
McElhatton PR, Sullivan FM, Volans GN. Paracetamol overdose in pregnancy:
analysis of the outcomes of 200 cases referred to the teratology information
service. Reproductive Toxicology 1997; 10:85–94.
Syme MR, Paxton JW, Keelan JA. Drug transfer and metabolism by the human
placenta. Clinical Pharmacokinetics 2004; 43(8):487–514.
Wiles JM, Clark LE, Herrera JL. Acetaminophen overdose in pregnancy. Southern
Medical Journal 2005; 98(11):1118–1122.
2.22 POISONING IN CHILDREN

Unintentional paediatric exposures generate over 80,000 calls to
Australian poisons information centres (PICs) each year. Many
children are also brought directly to emergency departments without
initial PIC consultation. The following information refers to
unintentional exposures in children under the age of 6 years. Older
children and adolescents may present with deliberate self-poisoning
and these cases are assessed and managed according to the principles
outlined for adults.
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MANAGEMENT
Resuscitation
Paediatric resuscitation in poisoning follows the principles outlined in
Chapter 1.2: Resuscitation. Attention to airway, breathing and circulation
are paramount and ensure survival in the vast majority of patients.
Risk assessment
The principles of risk assessment in acute paediatric poisoning are the
same as outlined for adults in Chapter 1.3: Risk assessment. However,
the process is influenced by the difficulty in obtaining an accurate history
regarding dose and agent, and the different range of agents ingested by
small children.
Paediatric unintentional exposures occur most frequently with
children in the 12–36 months age group. It is normal behaviour at that
age to ingest small items found in the immediate environment. Not
surprisingly, the range of agents ingested differs substantially from that 129
ingested by adolescents or adults who deliberately self-poison (see Table
2.22.1). The ingested agent is more likely to be non-pharmaceutical and
TOXICOLOGY HANDBOOK
often virtually non-toxic when ingested in the readily available dose (see
Table 2.22.2).
The toxic effects exerted by most agents on a mg/kg basis are the
same for children as for adults. Small children rarely ingest more than
2–3 tablets or a mouthful of most agents, which equates to doses well
below those ingested by adults or adolescents intending self-harm.
However, some pharmaceutical agents, particularly large-dose controlled-
release preparations, have the potential to cause serious toxicity if
ingested by a 10-kg toddler in one, two or three dose units (see Table
2.22.3). Some non-pharmaceutical agents are also potentially lethal to
children in small doses (see Table 2.22.4). In envenoming cases, the dose
of venom is determined by the venomous creature, not the victim, and
children receive a larger venom dose on a microgram/kg basis.
Agents that do not cause significant toxicity when ingested in one,
two or three dose units by small children include paracetamol (more than
TABLE 2.22.1 Agents involved in accidental paediatric exposures
Agent Percentage
Pharmaceuticals 40%
Household cleaning products 14%
Plants 13%
Cosmetics 10%
Pesticides 6%
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TABLE 2.22.2 Non-toxic household exposures
Antacids Inks
Antibiotics Laxatives
Bath oil Lipstick
Candles (wax) Matches (red phosphorus)
Chalk Newsprint
Cigarette butts Oral contraceptives
Colognes and perfumes Paint
Corticosteroids Shampoo
Cosmetics Shaving cream
Deodorants Shoe polish
Detergents (sips) Silica
Fertilisers Soap
Glues Suntan lotions
Hair products Thermometer mercury
Hand lotions Vaseline (petroleum jelly)
Incense
130
13
four 500-mg tablets, or more than 42 mL of 240 mg/5 mL solution

0
required to exceed 200 mg/kg), iron (six or more tablets containing

TOXICOLOGY HANDBOOK
105 mg elemental iron required to exceed 60 mg/kg), colchicine (10 or

more 0.5-mg tablets required to exceed 0.5 mg/kg), digoxin (16 or more
250-microgram tablets required to exceed 4 mg) and anticoagulant
rodenticides (less than one packet is generally considered non-toxic
following a single unintentional ingestion).
Unfortunately, accurate estimation of dose and time is frequently
challenging because of the inability to obtain an accurate dosing history.
Risk assessment and subsequent management decisions are always based
on a ‘worst-case scenario’ determined as follows:
1 The time of ingestion is assumed to be the latest possible time
(except paracetamol).
2 Assume all missing or unaccounted agent(s) have been ingested.
3 Do not attempt to account for spillage, which is difficult to estimate.
4 If more than one child is involved, it is assumed that each child
ingested all the missing or unaccounted agent(s).
This approach means that many children are assessed and observed
in hospital but do not go on to develop toxicity.
Ingestion of a few unidentified tablets, often found in a public space,
presents a difficult scenario around which to construct a risk assessment.
If a tablet remains available for inspection, a PIC may be consulted to
assist with identification. If this cannot be done with complete accuracy,
the risk assessment assumes that the ingested tablets are one of the
potentially lethal agents (see Table 2.22.3). A management plan based on
this risk assessment is shown in Table 2.22.5.
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TABLE 2.22.3 Pharmaceuticals with potential for severe toxicity if one
or two tablets ingested by a 10-kg toddler
Agent Features of severe toxicity
Amphetamines Agitation, confusion,

Amphetamine hypertension, hyperthermia
Methamphetamine
MDMA (ecstasy)
Baclofen 25 mg Coma
Calcium channel blockers Delayed onset of bradycardia,

Diltiazem CD 180, 240 or 360 mg hypotension, conduction
Verapamil SR 160, 180 or 240 mg defects, refractory shock
Carbamazepine 400 mg Coma
Chloroquine 155 mg Rapid onset of coma, seizures

Hydroxychloroquine 200 mg and cardiovascular collapse
131
Clozapine 100 or 200 mg Coma
Dextropropoxyphene 100 mg Ventricular tachycardia
TOXICOLOGY HANDBOOK
Opioids Coma, respiratory arrest
Oxycodone 5 mg, 10 mg, 20 mg, Note: Onset of toxicity may be
40 mg, 80 mg delayed with
Hydromorphone 2 mg, 4 mg, 8 mg diphenoxylate/atropine and
Methadone 10 mg controlled-release
Morphine sulfate 5, 10, 15, 30, 60, morphine
100, 200 mg (controlled release)
Diphenoxylate 2.5 mg/atropine 25
microgram
Propranolol 160 mg Coma, seizures, ventricular

tachycardia, hypoglycaemia
Sulfonylureas Hypoglycaemia; onset may be

Glibenclamide 5 mg delayed up to 8 hours
Glibenclamide/metformin 1.25/250 mg,
2.5/500 mg, 5/500 mg
Gliclazide 80 mg
Gliclazide modified-release 30 mg
Glimepiride 1, 2, 3, 4 mg
Glipizide 5 mg
Theophylline SR 200, 250, 300 mg Seizures, supraventricular

tachycardia, vomiting
Tricyclic antidepressants Coma, seizures, hypotension,

Dothiepin 75 mg ventricular tachycardia
Venlafaxine XR 150 mg Seizures

Adapted from McCoubrie D, Murray L, Daly FFS et al. Ingestion of two unidentified
tablets by a toddler. Emergency Medicine Journal 2006; 23:718–720.
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TABLE 2.22.4 Non-pharmaceuticals with potential for severe toxicity if
sip or mouthful ingested by a 10-kg toddler
Agent Features of severe toxicity
Organophosphate and carbamate Cholinergic symptoms

insecticides Seizures
Depressed level of consciousness
Paraquat/Diquat Oropharyngeal burns

Multiple organ failure
Pulmonary fibrosis
Hydrocarbons Rapid depressed level of

Solvents consciousness
Eucalyptus oil Seizures
Kerosene Aspiration pneumonia
Camphor Rapid depressed level of

consciousness
132 Seizures
13
Hypotension
2
Corrosives Gastro-oesophageal injury including

TOXICOLOGY HANDBOOK
Sodium hydroxide perforation

Strong acids
Naphthalene (one mothball) Methaemoglobinaemia

NB: Most mothballs contain Haemolysis
paradichlorobenzene, which is
non-toxic after a single
unintentional ingestion
Strychnine Rapid onset of generalised muscle

spasm
Death by respiratory failure
TABLE 2.22.5 Management of a toddler who ingests unidentified tablets
• Admit for a minimum 12-hour observation period

• Ensure healthcare facility has appropriate resources to observe,
resuscitate and treat patient if evidence of poisoning occurs
• IV access can be deferred until early evidence of toxicity is apparent
• Check bedside glucose level at presentation, if there is clinical evidence
of hypoglycaemia, and at discharge
• Brief staff regarding clinical features for which the patient is being
observed (see Table 2.22.3)
• Monitor level of consciousness, vital signs (pulse, blood pressure and
respiratory rate) and early clinical features of hypoglycaemia
• Cardiac monitoring may be instituted if there is any abnormality of
conscious state or vital signs
• Discharge patient only during daylight hours
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Supportive care and disposition
Most ingestions are benign and do not need referral to hospital or
gastrointestinal decontamination (see Table 2.22.2). For those ingestions
that require management in a hospital setting, risk assessment based on
the ‘worst-case scenario’ guides a defined period of focused observation.
Investigations
The screening tests performed on all adolescents and adults who
deliberately self-poison are not indicated in the context of unintentional
paediatric poisoning. Investigations are performed only for specific
purposes and are usually not necessary. Early measurement of drug
levels, such as paracetamol, digoxin or theophylline, may be useful to
exclude ingestion and obviate the need for prolonged observation, further
investigation or transfer between facilities.
Decontamination
133
Gastrointestinal decontamination following unintentional paediatric
ingestion is not routine. It is unusual that even the risk assessment based
on a ‘worst-case scenario’ implies potential benefits that outweigh the
TOXICOLOGY HANDBOOK
risk associated with gastrointestinal decontamination procedures in
children. Where activated charcoal is indicated, mixing with ice cream
improves its palatability and the ease of administration. Administration
of activated charcoal via a nasogastric tube inadvertently placed in the
bronchial tree has resulted in paediatric death. Decontamination should
be reserved for severe or life-threatening poisoning where the risk
assessment suggests that supportive care or antidote treatment alone may
not be adequate to ensure a satisfactory outcome.
Enhanced elimination and antidotes
Antidotes and enhanced elimination techniques have specific indications,
contraindications, methods of administration, monitoring requirements,
appropriate therapeutic end points and adverse effect profiles. The
risk–benefit analysis is rarely in favour of these interventions following
paediatric exposures. Doses of antidotes, where indicated, are usually the
same as for adults on a mg/kg basis. However, antivenom doses are the
same as for adults in absolute terms.
DISPOSITION AND FOLLOW-UP
The vast majority of paediatric exposures are benign and do not require
referral to hospital for assessment or observation. This decision based on
risk assessment is often made by a PIC when contacted by parents,
carers or medical professionals working outside of hospital; in less than
7% of such cases is the child referred to hospital by the PIC. Most
children referred or presenting to hospital can be discharged home if
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clinical evidence of toxicity does not develop within a short period of
observation. Those who develop toxicity require admission to a facility
able to provide an appropriate level of care.
Following any unintentional paediatric exposure, the circumstances
of exposure are evaluated and parents or carers advised on safe storage
of medicines and chemicals in the home if indicated. Unusually severe
intoxication suggesting large, repeated or unusual exposure prompts

consideration of non-accidental injury (NAI). This diagnosis is also
considered if poisoning is diagnosed in an infant under 12 months
of age. Children in this age group are not normally capable of self-
administering tablets or other foreign materials. They may be
administered toxins by adult carers with malicious intent, or by older
siblings.
References
Bar-Oz B, Levichek Z, Koren G. Medications that can be fatal for a toddler with one
134 tablet or teaspoonful. Pediatric Drugs 2004; 6:123–126.
Calello DP, Henretig FM. Pediatric toxicology: specialized approach to the poisoned
13
4
child. Emergency Clinics of North America 2014; 32:29–52.

McCoubrie D, Murray L, Daly FFS et al. Ingestion of two unidentified tablets by a
TOXICOLOGY HANDBOOK
toddler. Emergency Medicine Journal 2006; 23:718–720.

Mofenson HC, Greensher J, Carraccio TR. Ingestions considered non-toxic.
Emergency Medicine Clinics of North America 1984; 2(1):159–174.
2.23 POISONING IN THE ELDERLY

The assessment and management of the poisoned elderly patient is
challenging.
The coexistence of limited physiological reserves, deteriorating
cognition, multiple medical problems and their multiple prescribed
medications provides the basis for exaggerated and unpredictable
responses to any toxicological insult. The risk assessment for an
overdose in the elderly patient predicts a more severe clinical course for
the same agent taken in the same dose by a healthy young adult. Higher
levels of vigilance, supportive care and monitoring are necessary. The
clinical course of overdose or chronic poisoning is likely to be more
severe and also have a higher complication rate. Age is highly correlated
with case fatality rate and it is estimated that each 10-year increase in
age is associated with a 36% increase in the odds ratio for death as an
outcome following poisoning. Elderly patients are more likely to require
hospital care as a result of accidental exposures and adverse drug effects.
Pharmacokinetic changes with ageing include delayed gastrointestinal
absorption, decreased protein binding with resultant increased free drug
levels and reduced hepatic metabolic function and glomerular filtration
ERRNVPHGLFRVRUJ
rate with resultant impaired elimination. Acute renal failure secondary to
intercurrent medical problems or prescribed medications commonly leads
to poisoning syndromes in the elderly, such as chronic lithium or digoxin
toxicity.
Pharmacodynamic differences in the elderly are a result of drug
actions on physiologically impaired organs. This is particularly seen with
cardiovascular, respiratory and CNS depressant agents. An elderly
patient’s ability to respond to cardiovascular compromise with usual
mechanisms such as peripheral vasoconstriction and increased cardiac
output varies greatly. Clinical assessment of volume status in order to
optimise renal and cardiac function is often unreliable and a lower
threshold for invasive monitoring is required in these patients.
Most elderly patients will have a relatively delayed recovery from
serious poisoning. The complications of immobility and hospital
admission are observed more frequently in the elderly. These include
atelectasis, pneumonia, pulmonary embolism, catheter-induced sepsis,
muscle wasting and acute confusional states. 135
Reference
TOXICOLOGY HANDBOOK
Roger JJ, Heard K. Does age matter? Comparing case fatality rates for selected
poisonings reported to U.S. poison centers. Clinical Toxicology 2007;
45:705–708.
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CHAPTER 3
SPECIFIC TOXINS
3.1 Alcohol: Ethanol 140

3.2 Alcohol: Ethylene glycol 143
3.3 Alcohol: Isopropanol (isopropyl alcohol) 146
3.4 Alcohol: Methanol (methyl alcohol) 149
3.5 Alcohol: Other toxic alcohols 152
3.6 Amiodarone 155
3.7 Amisulpride 157
3.8 Amphetamines and other sympathomimetics 159
3.9 Angiotensin-converting enzyme inhibitors 164
3.10 Anticoagulant rodenticides 166
3.11 Anticonvulsants: Newer agents 169
3.12 Antihistamines (non-sedating) 172
3.13 Antihistamines (sedating) 174
3.14 Arsenic 177
3.15 Baclofen 180
3.16 Barbiturates 183
3.17 Benzodiazepines 187
3.18 Benztropine 190
3.19 Beta-blockers 191
3.20 Bupropion 194
3.21 Button batteries 197
3.22 Calcium channel blockers 200
3.23 Cannabinoids (marijuana) 205
3.24 Carbamazepine 208
3.25 Carbon monoxide 211
3.26 Chloroquine and hydroxychloroquine 215
3.27 Chloral hydrate 217
3.28 Clonidine 220
3.29 Clozapine 223
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3.30 Cocaine 225
3.31 Colchicine 229
3.32 Corrosives 232
3.33 Cyanide 236
3.34 Digoxin: Acute overdose 239
3.35 Digoxin: Chronic poisoning 243
3.36 Diphenoxylate–atropine 247
3.37 Gamma-hydroxybutyrate (GHB) 249
3.38 Glyphosate 252
3.39 Hydrocarbons 255
3.40 Hydrofluoric acid 258
3.41 Hydrogen peroxide 262
3.42 Insulin 265
3.43 Iron 269
3.44 Isoniazid 273
3.45 Lead 275
3.46 Lithium: Acute overdose 279
3.47 Lithium: Chronic poisoning 282
3.48 Local anaesthetic agents 284
3.49 Mercury 288
3.50 Metformin 292
3.51 Methotrexate 295
3.52 Mirtazapine 298
3.53 Monoamine oxidase inhibitors (MAOIs) 300
3.54 New oral anticoagulants 304
3.55 Non-steroidal anti-inflammatory drugs (NSAIDs) 308
3.56 Olanzapine 311
3.57 Opioids 314
3.58 Organochlorines 319
3.59 Organophosphorus agents (organophosphates
and carbamates) 322
3.60 Paracetamol: Acute overdose 327
3.61 Paracetamol: Modified-release formulations 336
3.62 Paracetamol: Repeated supratherapeutic
ingestion 340
3.63 Paraquat 343
3.64 Phenothiazines and butyrophenones
(antipsychotic agents) 349
3.65 Phenytoin 351
3.66 Potassium chloride 354
3.67 Quetiapine 357
3.68 Quinine 360
3.69 Risperidone 363
3.70 Salicylates 365
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3.71 Selective serotonin reuptake inhibitors (SSRIs) 369
3.72 Strychnine 373
3.73 Sulfonylureas 375
3.74 Theophylline 378
3.75 Thyroxine 383
3.76 Tramadol 385
3.77 Tricyclic antidepressants (TCAs) 387
3.78 Valproic acid (sodium valproate) 391
3.79 Venlafaxine and desvenlafaxine 395
3.80 Warfarin 399
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3.1 ALCOHOL: ETHANOL
See also Chapter 2.12: Alcohol use disorder.
Ethanol causes CNS depression that is synergistic with other CNS
depressants and potentially lethal. It is frequently co-ingested with other
agents during deliberate self-poisoning and the history of alcohol
co-ingestion may not be forthcoming unless specific enquiry is made.
Care is supportive.
RISK ASSESSMENT
• Ethanol ingestion causes rapid, dose-related CNS depression,
SPECIFIC TOXINS
with a high degree of inter-individual variability.

• Dose may be estimated if the number of standard drinks consumed
is known:
— Standard drinks containing approximately 10 g ethanol:
– 375-mL can of mid-strength beer (3.5%)
– 100-mL glass of wine
– 30-mL shot of spirit.
• Co-ingestion of other CNS depressants (e.g. sedative-hypnotic
agents, antidepressants, opioids) increases the risk of respiratory
140 depression.
• Seizures may occur in the setting of ethanol intoxication or
14
0
withdrawal.
TOXICOLOGY HANDBOOK
Toxic mechanism
The molecular sites of action are uncertain. Augmentation of the GABAA receptor
complex is thought to be central to its CNS depressant effects. Glycine, N-methyl-D-
aspartate, serotonin (5-HT3), adenosine and L-type calcium channel effects also appear
to be involved. In addition, ethanol causes dose-dependent cardiovascular depression
and impairs gluconeogenesis, thus causing hypoglycaemia in susceptible individuals (e.g.
children, patients with cirrhosis of the liver).
Toxicokinetics
Ethanol is rapidly absorbed following oral administration. It distributes readily across the
total body water (volume of distribution 0.6 L/kg). Ethanol is oxidised by cytosolic and
microsomal alcohol dehydrogenases to form acetaldehyde, which in turn is metabolised
by aldehyde dehydrogenase to acetate (see Appendix 4: Alcohol pathways). Both
cytosolic steps involve the reduction of NAD to NADH. Above a serum ethanol
concentration of 4 mmol/L (2 mg/dL), zero order kinetics applies, so a constant amount
of ethanol is metabolised per unit time. In most patients, serum ethanol levels decrease
by approximately 4 mmol/L/hour (20 mg/dL/hour; 0.02%/hour). The production of NADH
decreases conversion of lactate to pyruvate (hyperlactataemia), and inhibits
gluconeogenesis and fatty acid oxidation (hypoglycaemia).
CLINICAL FEATURES
Clinical features are progressive with increasing degrees of
intoxication (see Table 3.1.1).
• Disinhibition, emotional lability and euphoria
• Nystagmus, ataxia, slurred speech
• Agitation, aggression and disorientation
• Nausea, vomiting
• Tachycardia, hypotension, hypothermia
• Coma with loss of airway protective reflexes, respiratory
depression and hypotension
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TABLE 3.1.1 Guide to dose-related serum ethanol concentrations and
clinical features
Serum ethanol concentration

Ethanol Conventional units
dose SI units
(g/kg) (mmol/L) mg/dL g/dL (%) Clinical features
0.5 11 50 0.05 Disinhibition and euphoria
1 22 100 0.10 Slurred speech. Impaired

judgement and
coordination.
SPECIFIC TOXINS
Significant CNS depression
in non-tolerant
individuals, especially
children
2 43 200 0.20 Potential for coma, although

ethanol-dependent
individuals are usually
ambulant
141
>5 >87 >400 >0.40 Coma, respiratory
depression,
hypotension, except in
TOXICOLOGY HANDBOOK
patients with marked
tolerance
Note: To convert SI units to mg/dL, multiply by 4.61. To convert mg/dL to SI units,
multiply by 0.22.
Improvement in conscious state is usually seen within 2–4 hours, but 6–12
hours may elapse before patients are ambulant.
INVESTIGATIONS
Screening tests in deliberate self-poisoning
• 12-lead ECG, BGL and paracetamol level
Specific investigations as indicated
• Serum, blood and breath alcohol levels.
• Serum ethanol levels assist risk assessment in patients with
CNS depression. However, elevated serum ethanol
concentrations cannot be assumed to be the sole contributor
to CNS depression and an appropriate evaluation for other
causes is required.
• Serum ethanol concentration is not the same as whole blood
ethanol level, which defines legal driving limits. Whole blood
concentrations are approximately 10% lower than corresponding
serum concentrations.
• Breath ethanol estimation provides a convenient bedside
estimation of blood ethanol concentration but the result is
influenced by minute ventilation.
ERRNVPHGLFRVRUJ
MANAGEMENT
• Attention to airway, breathing and circulation are paramount.
These priorities are managed along conventional lines as outlined
• Basic resuscitative measures ensure the survival of the vast
majority of patients.
• General supportive care measures are indicated, as outlined in
Chapter 1.4: Supportive care and monitoring.
• Give thiamine 200 mg PO or IV tds to patients with potential
thiamine deficiency.
• Close clinical and physiological monitoring is indicated.
• Monitor for urinary retention and place an indwelling urinary
SPECIFIC TOXINS
catheter as required.
Decontamination
• Activated charcoal does not bind ethanol and is not indicated.
• Elimination of ethanol is enhanced by haemodialysis. However, as
a good outcome is ensured with thorough supportive care, this
intervention is not routinely indicated.
142 Antidotes
14
• None available.
2
TOXICOLOGY HANDBOOK

• Patients with mild CNS depression are managed supportively in a
ward environment. When the patient is cooperative, clinically well,
ambulant, passing urine, eating and drinking, discharge may
occur.
• Patients with significant CNS depression require intubation and
admission to an intensive care unit.
• Where appropriate, patients are counselled regarding ethanol
abuse prior to discharge, as discussed in Chapter 2.12: Alcohol
use disorder.
HANDY TIPS
• A serum ethanol concentration confirms the diagnosis of
ethanol intoxication but does not exclude other causes of
CNS depression (e.g. co-ingestion, trauma, metabolic
disorder).
• Anticipate alcohol withdrawal during the observation period in
patients with alcohol dependence.
PITFALLS
• Failure to regard ethanol intoxication as potentially life
threatening
• Failure to detect and manage coexisting intoxications or other
medical conditions in the ethanol intoxicated patient
• Discharge of ethanol intoxicated patients before they are
competent to make decisions about their own welfare and ensure
their own safety
ERRNVPHGLFRVRUJ
Presentations
Ethanol is found in varying concentrations in a large number of beverages, and domestic
and commercial products:
Beers: 2.8–12.0%
Wines: 9–14%
Spirits: 35–50%
Methylated spirits: 95%
Mouth wash, food extracts and flavourings (e.g. vanilla extract 35% ethanol), cough and
cold syrups, perfumes and cosmetics.
References
Baselt RC. Disposition of toxic drugs and chemicals in man. 5th edn. Foster City,
California: Chemical Toxicology Institute; 2000.
Lieber CS. Medical disorders of alcoholism. New England Journal of Medicine 1995;
SPECIFIC TOXINS
333(16):1058–1065.
O’Connor PG, Schottenfeld RS. Patients with alcohol problems. New England Journal of
Medicine 1998; 338(9):592–602.
Tjipto AC, Taylor DMcD, Liew H. Alcohol use among young adults presenting to the
emergency department. Emergency Medicine Australasia 2006; 18(2):125–130.
3.2 ALCOHOL: ETHYLENE GLYCOL

Ethylene glycol (EG) is a toxic alcohol. Deliberate self-poisoning is 143
usually lethal without timely intervention.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
• Ingestion of >1 mL/kg (1 g/kg) is potentially lethal.
• All deliberate self-poisonings are assumed to be potentially lethal.
• Unintentional ingestion of less than a mouthful is benign and does
not require hospital evaluation unless symptoms develop.
• Co-ingestion of ethanol complicates risk assessment (see
Investigations below).
• Dermal and inhalation exposure does not lead to EG intoxication.
• Children: minor ingestions such as a taste or lick do not require
hospital evaluation unless symptoms develop.
Toxic mechanism
Ethylene glycol causes CNS effects similar to those of ethanol. The more important toxic
effects are due to metabolites rather than the parent compound. A severe anion gap
metabolic acidosis develops secondary to accumulation of glycolic acid and lactate
(increased NADH and decreased conversion of lactate to pyruvate). Calcium oxalate
crystals form in tissues, including renal tubules, myocardium, muscles and brain.
Hypocalcaemia follows. Acute oliguric renal failure occurs secondary to the nephrotoxic
effects of both glycolic acid and calcium oxalate.
Toxicokinetics
Ethylene glycol is rapidly absorbed following ingestion. Peak concentrations occur within
1–2 hours. It is distributed across the total body water with rapid CNS penetration.
Ethylene glycol is metabolised sequentially by alcohol dehydrogenase (ADH) and
aldehyde dehydrogenase (ALDH) to glycoaldehyde and glycolic acid, which in turn is
converted to glyoxylic acid and oxalic acid (see Appendix 4: Alcohol pathways). In the
absence of ADH inhibition (ethanol or fomepizole) the elimination half-life of EG is 3–9
hours. Ethanol in a serum concentration of 11–22 mmol/L (50–100 mg/dL) competitively
inhibits ADH preventing metabolism of EG to glycoaldehyde. Elimination half-life
increases to 14–17 hours, as EG has to be eliminated exclusively by the kidney.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
• The clinical course of EG intoxication is often described as
occurring in three stages (CNS, cardiopulmonary and renal), but
these are artificial descriptions of a rapid clinical course.
• Initial clinical features develop within the first 1–2 hours and are
similar to those of ethanol intoxication:
— Euphoria, nystagmus, drowsiness, nausea and vomiting.
• Progressively severe features develop over the subsequent
4–12 hours:
— Dyspnoea, tachypnoea, tachycardia, hypertension and
decreased conscious level progressing to shock, coma,
seizures and death.
• Flank pain and oliguria indicate acute renal failure.
SPECIFIC TOXINS
• Late cranial neuropathies (involving cranial nerves II, V, VII, VIII, IX,
X and XII) are described up to 5–20 days later.
INVESTIGATIONS
Specific investigations
• EUC (including chloride), serum lactate, serum osmolality, arterial
144 blood gases and calcium, magnesium and phosphate levels
— Elevated osmolar gap, anion gap acidosis and
14
4
hyperlactataemia are surrogate markers of intoxication.

— Venous bicarbonate concentration is a useful surrogate
TOXICOLOGY HANDBOOK
marker of intoxication in the asymptomatic patient if ABGs are

not available.
— Anion gap acidosis with elevated lactate (± elevated osmolar
gap), associated with hypocalcaemia and rising creatinine, is
pathognomonic of EG intoxication.
— An elevated serum lactate level must be interpreted with care
as some laboratory assays do not differentiate between
lactate and glycolate.
— See Chapter 2.18: Osmolar gap and Chapter 2.19: Acid–
base disorders for discussion of interpreting acid–base
disturbances, anion and osmolar gaps.
• Breath or serum ethanol level
— Required to determine whether there has been co-ingestion of
ethanol, or to titrate ethanol treatment.
• Serum EG level
— Not readily available at most locations in a clinically useful
timeframe. Where available, it provides definitive confirmation
of EG intoxication.
• Urine microscopy
— Presence of calcium oxalate crystals in the urine is
pathognomonic of ethylene glycol intoxication but their
absence does not exclude the diagnosis.
MANAGEMENT
These priorities are managed along conventional lines, as outlined
ERRNVPHGLFRVRUJ
• Patients with severe EG intoxication are acidaemic with a degree
of respiratory compensation:
— Intubation without maintaining hyperventilation exacerbates
acidaemia and may result in an acute decompensation, and
even death
— Maintain hyperventilation and consider bolus IV sodium
bicarbonate 1–2 mmol/kg to prevent worsening of acidaemia
pending haemodialysis.
• Treat seizures with IV benzodiazepines as discussed in Chapter
2.6: Seizures.
• Detect and correct hypoglycaemia, hyperkalaemia and
hypomagnesaemia. Correct hypocalcaemia only if there are
refractory seizures or prolonged QT.
SPECIFIC TOXINS
• Monitor fluid balance and urine output.
Decontamination
• Gastrointestinal decontamination is not indicated.
• Haemodialysis is the definitive management of EG intoxication.
During haemodialysis, the elimination half-life of EG is reduced to
2.5–3.5 hours, depending on flow rates. 145
• Lactate-free dialysates with added bicarbonate may assist
correction of acidaemia.
• Indications for haemodialysis:
TOXICOLOGY HANDBOOK
— History of large EG ingestion with osmolar gap >10
— Acidaemia with pH <7.30
— Acute renal failure
— Ethylene glycol level >8 mmol/L (50 mg/dL) if available.
• End points for haemodialysis:
— Correction of acidosis
— Osmolar gap <10
— Ethylene glycol level <3.2 mmol/L (20 mg/dL) if available.
• Acid–base status and electrolytes are repeated every 4 hours for
12 hours following cessation of haemodialysis to confirm that
further dialysis is not required.
Antidotes
• Ethanol (see Chapter 4.8: Ethanol) and fomepizole (see Chapter
4.11: Fomepizole) are used in the treatment of suspected or
confirmed EG poisoning as temporising measures while awaiting
haemodialysis.
• Note: Fomepizole is not currently registered in Australasia.
• Children who remain clinically well after suspected unintentional
ingestion and have a normal venous bicarbonate level
(≥20 mEq/L) at 4 or more hours post-ingestion, may be
discharged.
• Adult patients who remain clinically well following accidental
ingestion and have a normal venous bicarbonate level
(≥20 mEq/L) 4 hours after serum or breath ethanol level is
demonstrated to be undetectable, are fit for medical discharge.
ERRNVPHGLFRVRUJ
• All symptomatic patients, and those with deliberate ingestion, are
assumed to have potentially lethal EG intoxication, and are
admitted to hospital for further evaluation and definitive
management if required.
• If established renal failure develops, ongoing dialysis may be
required for several weeks but renal function usually returns to
normal.
• Patients who survive severe intoxication are followed up to
exclude the development of cranial neuropathies.
HANDY TIPS
• Co-ingestion of ethanol delays the onset of clinical features of EG
intoxication.
•
SPECIFIC TOXINS
Plan for transfer to a facility with haemodialysis as soon as the

provisional diagnosis of EG intoxication is made.
PITFALLS
• Absence of symptoms does not exclude a significant ingestion.
• Normal osmolar gap (<10) does not exclude significant
intoxication.
• False reliance on normal serum bicarbonate level to exclude
significant ingestion when ADH is blocked by ethanol.
146
14
CONTROVERSY
6
• Therapy with fomepizole alone may obviate the need for

TOXICOLOGY HANDBOOK
haemodialysis in selected cases of ethylene glycol intoxication.
Sources
Radiator coolants and antifreeze in concentrations 20–98%
De-icing solutions
Solvents
Brake fluids
References
Barceloux DG, Krenzelok EP, Olsen K et al. Ad Hoc Committee on the Treatment
Guidelines for Ethylene Glycol Poisoning on behalf of the American Academy of
Clinical Toxicology. American Academy of Clinical Toxicology. Practice guidelines
on the treatment of ethylene glycol poisoning. Clinical Toxicology 1999; 37(5):
537–560.
Caravati EM, Erdman AR, Christianson G et al. Ethylene glycol exposure: an evidence
based consensus guideline for out-of-hospital management. Clinical Toxicology
2005; 43:327–345.
Jolliff HA, Dart RC, Bogdan GM et al. Can the diagnosis of ethylene glycol (EG) toxicity
be made without serum EG levels and osmolality values (abstract)? Journal of
Toxicology–Clinical Toxicology 2000; 38(5):539–540.
3.3 ALCOHOL: ISOPROPANOL (isopropyl alcohol)

Isopropanol produces a CNS intoxication syndrome identical to that
of ethanol, but is more potent. It causes marked gastrointestinal
irritation and ketosis without directly causing acidosis. Management is
supportive.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Isopropanol causes dose-related CNS depression following
ingestion, although there is a high degree of inter-individual
variability.
• As little as 1 mL/kg of a 70% solution causes symptoms of
inebriation and more than 4 mL/kg may cause coma and
respiratory depression.
• Co-ingestion of other CNS depressants (e.g. sedative-hypnotic
agents, opioids) increases the risk of respiratory depression.
hospital evaluation unless symptoms develop. Ingestions of
>3 mL are associated with symptoms of CNS depression within
SPECIFIC TOXINS
2 hours and warrant hospital evaluation. Significant isopropanol
toxicity is reported from dermal absorption following application
of ‘rubbing alcohol’ to small children as an antipyretic measure.
Toxic mechanism
As with ethanol, the molecular sites of action of isopropanol are uncertain. Augmentation
of the GABAA receptor complex is thought to be central to effects. Production of acetone
and severe ketonaemia may contribute to CNS depression. Severe anion gap acidosis is
not a feature of isopropanol intoxication, as acetone is not further metabolised to any
great extent. Isopropanol is a gastrointestinal irritant and causes dose-dependent
cardiovascular depression.
147
Toxicokinetics
Isopropanol is rapidly and well absorbed following ingestion, dermal contact or
TOXICOLOGY HANDBOOK
inhalation. It distributes rapidly across the total body water with volume of distribution
0.6 L/kg. Forty per cent of an absorbed dose is excreted unchanged by the lungs and
kidneys. The rest is metabolised by hepatic ADH to form acetone. Acetone is mostly
excreted unchanged via the lungs and, to a lesser extent, the kidneys. The affinity of
ADH for isopropanol is much less than for ethanol and elimination of isopropanol is
correspondingly slower (elimination half-life up to 16 hours). Acetone frequently
accumulates during isopropanol intoxication.
CLINICAL FEATURES
• An intoxication syndrome identical to ethanol develops rapidly
following ingestion.
• Loss of airway protective reflexes, respiratory depression and
hypotension accompany coma.
• The duration of inebriation is longer than following ethanol
ingestion.
• Ketosis may be indicated by the breath odour of acetone.
INVESTIGATIONS
• EUC (including Cl−), serum osmolality, serum acetone level, ABG
— Elevated osmolar gap in the absence of severe anion gap
acidosis suggests isopropanol intoxication (beware this may
also occur with ethylene glycol and methanol intoxication that
presents early or with co-ingestion of ethanol).
ERRNVPHGLFRVRUJ
— Isopropanol levels are not routinely available and do not assist
management.
— Serum acetone level is elevated and qualitative serum ketones
are positive.
— Serum acetone levels greater than 100 mg/dL can falsely
elevate serum creatinine.
• Urinalysis for ketones
MANAGEMENT
SPECIFIC TOXINS
• Give thiamine 200 mg IV tds to patients with potential thiamine
deficiency.
• Monitor for urinary retention and place an indwelling urinary
catheter if required.
148
Decontamination
14
• Activated charcoal is not indicated.

8
TOXICOLOGY HANDBOOK
• Haemodialysis is highly effective at removing isopropanol but is
rarely indicated as a good outcome can be anticipated with
supportive care.
Antidotes
• None available.
• Patients with mild CNS depression are managed supportively and
discharged when clinically well.
intensive care admission.
HANDY TIP
• Isopropanol intoxication mimics ethanol intoxication.
Sources
Isopropanol (50–70% concentration) is found in hand sanitisers, disinfectants, solvents,
window cleaners and perfumes.
References
Baselt R. Disposition of toxic chemicals and drugs in man. 5th edn. Foster City,
Stremski E, Hennes H. Accidental isopropanol ingestion in children. Pediatric Emergency
Care 2000; 16(4):238–240.
Zaman F, Pervez A, Abreu K. Isopropyl alcohol intoxication: a diagnostic challenge.
American Journal of Kidney Diseases 2002; 40(3):E12.
ERRNVPHGLFRVRUJ
3.4 ALCOHOL: METHANOL (methyl alcohol)
Methanol is a toxic alcohol. Poisoning frequently occurs following
ingestion of home-made distilled spirits (homebrew/moonshine/bootleg
liquor) or adulterated commercially available drinks, particularly from
countries with poor regulatory environments. Deliberate self-poisoning is
usually lethal without appropriate intervention.
RISK ASSESSMENT
• Ingestion of >0.5 mL/kg of 100% methanol is potentially lethal.
• Deliberate self-poisonings are assumed to be potentially lethal.
• Ingestion of less than a mouthful is benign and does not require
SPECIFIC TOXINS
• Co-ingestion of ethanol complicates risk assessment (see
Investigations below).
• Dermal or inhalational exposure is unlikely to lead to methanol
intoxication although it is reported in the context of inhalational
solvent abuse using carburettor cleaning fluid.
• Children: minor ingestions such as a taste or lick do not
require hospital evaluation unless symptoms develop.
Ingestion of >0.25 mL/kg (2.5 mL in a 10-kg toddler) can 149
theoretically lead to development of toxicity requiring specific
management.
TOXICOLOGY HANDBOOK
Toxic mechanism
Production and accumulation of formic acid produces a severe anion gap acidosis and
direct cellular toxicity due to inhibition of cytochrome oxidase. Retinal injury and oedema
leads to blindness. In the brain, subcortical white matter haemorrhages and putamenal
oedema classically occur. Late hyperlactataemia occurs due to inhibition of cellular
oxidative metabolism.
Toxicokinetics
Methanol is rapidly absorbed after ingestion with peak levels occurring within 30–60
minutes. Dermal and inhalational absorption occur, but reports of intoxication are rare.
It is rapidly distributed across the total body water with a volume of distribution of
0.7 L/kg. Methanol is metabolised in the liver by alcohol dehydrogenase (ADH) to
formaldehyde, which in turn is metabolised by aldehyde dehydrogenase (ALDH) to formic
acid (see Appendix 4: Alcohol pathways). The elimination half-life is 24 hours. Ethanol
in a serum concentration of 22 mmol/L (100 mg/dL; 0.1%) competitively inhibits ADH so
that methanol cannot be metabolised to formaldehyde. Methanol elimination half-life
increases to 48 hours, as methanol is eliminated exclusively by the kidney and
pulmonary routes.
CLINICAL FEATURES
• Mild CNS depression similar to that of ethanol intoxication is
evident within 1 hour of ingestion. Nausea, vomiting and
abdominal pain may occur.
• Following a latent period of 12–24 hours, symptoms of headache,
dizziness, vertigo, dyspnoea, blurred vision and photophobia
develop.
• Features of severe intoxication include tachypnoea, drowsiness
and blindness.
ERRNVPHGLFRVRUJ
• Progressive obtundation leading to coma and seizures heralds the
onset of cerebral oedema. Papilloedema is characteristic with
progressive demyelination and up to one-third of patients suffer
irreversible visual complications.
• Those who recover from serious CNS toxicity frequently display
extrapyramidal movement disorders.
INVESTIGATIONS
• EUC (including chloride), serum lactate, serum osmolality and
arterial or venous blood gases
SPECIFIC TOXINS
— Anion gap acidosis, hyperlactataemia and elevated osmolar

gap are surrogate markers of intoxication.
marker of intoxication in the asymptomatic patient if ABGs are
not available.
150 • Breath or serum ethanol level
15

0
• Serum methanol levels

TOXICOLOGY HANDBOOK
— Not usually readily available in a clinically useful timeframe.

• Radiology
— Brain CT scan demonstrates characteristic ischaemic or
haemorrhagic injury to the basal ganglia in patients with
permanent neurological sequelae.
MANAGEMENT
• Patients with severe methanol intoxication are acidaemic with a
degree of respiratory compensation:
acidaemia and may result in an acute decompensation, or
even death
pending haemodialysis
— Systemic acidosis enhances formic acid inhibition of
cytochrome oxidase. If pH <7.30 administer bicarbonate in
50 mmol aliquots to raise the pH above this level.
• Treat seizures with IV benzodiazepines, as discussed in Chapter
2.6: Seizures.
ERRNVPHGLFRVRUJ
• Cofactor therapy: Folinic acid or Folic acid is given at 50 mg IV
every 6 hours and continued until poisoning is definitively treated
(see Chapter 4.10: Folinic acid).
Decontamination
• Haemodialysis is the definitive management of methanol
intoxication. It removes methanol and formic acid and corrects
acidosis.
• Lactate-free dialysate with added bicarbonate may assist
correction of acidaemia.
• Indications for haemodialysis:
SPECIFIC TOXINS
— Any patient who fulfils criteria for ADH blockade
— Acidaemia with pH <7.3
— Visual symptoms
— Renal failure
— Deterioration of vital signs or electrolyte status despite
supportive care
— Methanol level >16 mmol/L (50 mg/dL) if available.
• End points for haemodialysis: 151
— Correction of acidosis
— Osmolar gap <10
— Methanol level <6 mmol/L (20 mg/dL) if available.
• Acid–base status and electrolytes are repeated every 4 hours for
TOXICOLOGY HANDBOOK
12 hours following cessation of haemodialysis to confirm that
further dialysis is not required.
Antidotes
4.11 Fomepizole) are used in the treatment of suspected or
confirmed methanol poisoning as temporising measures while
awaiting haemodialysis.
ingestion, and have a normal venous bicarbonate level
discharged.
• All symptomatic patients, and those with deliberate ingestion,
are assumed to have potentially lethal methanol intoxication,
and are admitted to hospital for further evaluation and
management.
HANDY TIPS
• ‘Methylated spirits’ available in Australasia do not contain
methanol.
ERRNVPHGLFRVRUJ
• Co-ingestion of ethanol delays the onset of clinical features of
methanol intoxication.
• Plan for transfer to a facility with haemodialysis as soon as the
provisional diagnosis of methanol intoxication is made.
• Serum bicarbonate levels provide a surrogate marker of formic
acid production.
PITFALLS
• Absence of symptoms does not exclude a significant
ingestion.
intoxication.
SPECIFIC TOXINS
CONTROVERSY
• Therapy with fomepizole alone may obviate the need for
haemodialysis in selected cases of methanol intoxication.
Sources
Carburettor cleaning fluid
Chemical applications in industry and science
Solvent in thinners, varnishes, paints and enamels
Model aeroplane and car fuel
152 Fuel additive
15
Dyes and stains

2
Racing car fuel

TOXICOLOGY HANDBOOK
Home-made or adulterated distilled spirits

Wood alcohol, wood spirits
References
Barceloux DG, Bond R, Krenzelok EP et al. American Academy of Clinical Toxicology
practice guidelines on the treatment of methanol poisoning. Journal of Toxicology–
Clinical Toxicology 2002; 40(4):415–446.
Kostic MA, Dart RC. Rethinking the toxic methanol level. Journal of Toxicology–Clinical
Toxicology 2003; 41(6):793–800.
3.5 ALCOHOL: OTHER TOXIC ALCOHOLS

Benzyl alcohol, Diethylene glycol, Dipropylene glycol, Ethylene glycol
monobutyl ether (EGBE), Ethylene glycol monoethyl ether (EGME),
Propylene glycol, Triethylene glycol
These alcohols are found in a variety of automotive products,
solvents and pharmaceuticals. Deliberate self-poisoning is potentially
lethal.
RISK ASSESSMENT
• Accidental oral ingestions do not cause significant toxicity.
• Deliberate self-poisonings are assumed to be potentially lethal.
• Ingestion of >1 mL/kg of 100% diethylene glycol is potentially
lethal.
• Ingestion of >0.5 mL/kg of glycol ether (EGBE or EGME) is
potentially lethal.
ERRNVPHGLFRVRUJ
• The toxic effects of propylene glycol are a function of dose and
rate of administration.
• Dermal and inhalation exposures do not lead to intoxication.
Toxic mechanism
These alcohols cause CNS effects similar to those of ethanol. More significant toxicity is
a consequence of accumulation of metabolites, including lactate. Diethylene glycol
metabolism also indirectly leads to lactic acidosis. The cardiovascular and CNS effects
of propylene glycol appear to be a direct toxic action.
Toxicokinetics
These alcohols are rapidly absorbed following ingestion and peak levels occur within
SPECIFIC TOXINS
1 hour. They are distributed across total body water with volumes of distribution of
0.6 L/kg. They are metabolised sequentially by hepatic alcohol dehydrogenase (ADH) to
pyruvate and lactate (propylene glycol), and aldehyde dehydrogenase (ALDH) to various
alkoxy acetic acid products.
CLINICAL FEATURES
• Initial clinical features develop within the first 1–2 hours and are
similar to those of ethanol intoxication: euphoria, nystagmus,
drowsiness, nausea and vomiting.
• Progressively severe features develop over subsequent 153
hours as metabolism progresses and lactic acidosis
worsens.
• Severe effects include coma, seizures, refractory shock and renal
TOXICOLOGY HANDBOOK
failure.
• Onset of severe toxicity may be delayed up to 48 hours following
ingestion of glycol ethers (EGBE, EGME).
• Over-rapid intravenous administration of excessive propylene
glycol (administration of large quantities of drug with propylene
glycol as a diluent) is associated with sudden cardiovascular
collapse.
INVESTIGATIONS
• EUC (including chloride), serum lactate, serum osmolality and
arterial or venous blood gases
— Anion gap acidosis, hyperlactataemia and elevated osmolar
gap are surrogate markers of intoxication.
marker of intoxication if ABGs are not available.
• Breath or serum ethanol level
• Serum toxic alcohol levels
— Not readily available in a clinically useful timeframe.
ERRNVPHGLFRVRUJ
MANAGEMENT
• Patients with severe toxic alcohol poisoning are acidaemic with a
degree of respiratory compensation.
acidaemia and may result in an acute decompensation, or
even death.
pending haemodialysis.
SPECIFIC TOXINS
• Treat seizures with IV benzodiazepines, as discussed in Chapter

2.6: Seizures.
• Severe acidaemia with pH <7.0 is corrected with IV sodium
bicarbonate pending haemodialysis.
154 Decontamination
15
4
TOXICOLOGY HANDBOOK
Haemodialysis is highly effective at removing toxic alcohols and the

resultant acids. Indications include:
• Serum pH <7.3
• Serum bicarbonate <20 mEq/L
• Osmolar gap >10
• Worsening severe lactic acidosis despite supportive care
• Deteriorating vital signs despite supportive care.
Antidotes
4.11 Fomepizole) are used in the treatment of glycol ether
(EGBE, EGME) poisoning prior to definitive treatment with
haemodialysis in the same way as they are for ethylene glycol
poisoning.
• The role of these antidotes in other toxic alcohol poisoning is not
established.
discharged.
ERRNVPHGLFRVRUJ
• All symptomatic patients, and those with deliberate ingestion, are
assumed to have potentially lethal intoxication and are admitted
to hospital for further evaluation and management.
HANDY TIP
• Serum bicarbonate and arterial pH are the chief surrogate
markers of toxic acid production.
PITFALLS
• Absence of symptoms does not exclude a significant
ingestion.
intoxication.
•
SPECIFIC TOXINS
Failure to recognise the potential for delay in development of
toxicity in glycol ether and diethylene glycol ingestions.
CONTROVERSY
• The efficacy of and indications for haemodialysis and antidote
therapy in the management of these toxic alcohols are not well
defined.
Sources
Diethylene glycol: hydraulic fluids, solvents 155
Glycol ethers (ethylene glycol monoethyl ether EGME, ethylene glycol monobutyl ether
EGBE): brake fluids, cleaning products, many solvents
Propylene glycol: solvents, many parenteral drug formulations
TOXICOLOGY HANDBOOK
Benzyl alcohol: bacteriostatic agent frequently found in parenteral drug formulations
References
Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe
toxic alcohol poisonings. Intensive Care Medicine 2005; 31:189–195.
Schep LJ, Slaughter RJ, Temple WA et al. Diethylene glycol poisoning. Clinical
Toxicology 2009; 47(6):525–535.
3.6 AMIODARONE
Acute ingestion uncommonly produces toxicity, irrespective of the dose.
Chronic toxicity is common.
RISK ASSESSMENT
• Acute oral overdose is usually benign, regardless of the dose
ingested.
• Delayed cardiac effects, including hypotension, atrial flutter and
T wave inversion, have been reported. The clinical features
associated with chronic toxicity are not observed following acute
overdose.
• There are no reported fatalities from acute oral overdose.
• Chronic toxicity is common and clinical manifestations include:
— Pulmonary toxicity
— Cardiovascular effects (bradycardia, AV blocks, torsades de
pointes, hypotension and negative inotropy)
— Thyroid dysfunction (hypo-/hyperthyroidism)
ERRNVPHGLFRVRUJ
— Hepatic toxicity
— Corneal micro-deposits.
• Children: ingestion of one or two tablets does not cause
symptoms and does not require hospital assessment.
Toxic mechanism
In addition to its predominant Vaughan-Williams class III effects, amiodarone also has
class I, II and IV properties. Its principal class III effects are secondary to blockade of
potassium channels, which prolong phase 4 of the cardiac action potential and the
refractory period of atrial and ventricular tissue.
Toxicokinetics
Oral bioavailability is variable but generally poor. Almost completely protein bound, it
has a large volume of distribution (65 L/kg). Amiodarone undergoes first-pass
SPECIFIC TOXINS
metabolism by cytochrome p450 to produce an active metabolite, desethylamiodarone.

Elimination is predominantly biliary and very slow: up to 80 hours following acute
ingestions and up to 100 days for chronic therapy (similar slow elimination for the active
metabolite).
CLINICAL FEATURES
Patients are usually asymptomatic, but delayed onset (more than
24 hours) of bradycardia, hypotension and self-limiting atrial
tachydysrhythmias has been reported.
156
15
INVESTIGATIONS
6

TOXICOLOGY HANDBOOK

• Serial ECGs for 24 hours
MANAGEMENT
• Resuscitation is rarely required and management is entirely
supportive.
• Cardiovascular effects can be delayed. Cardiac monitoring for
24 hours is recommended.
• Bradycardia can be resistant to atropine and may require
adrenaline, isoprenaline or pacing.
• Hypotension responds to vasopressors.
Decontamination
• Consider single-dose activated charcoal if presentation is within
2 hours.
• Not clinically useful.
Antidotes
• None available.
• Admit for 24 hours of cardiac monitoring. Patients may be
medically cleared if asymptomatic and have a normal ECG at the
end of that time.
ERRNVPHGLFRVRUJ
CONTROVERSY
• Duration of monitoring of an asymptomatic patient. The risk of
significant cardiac toxicity is low but could theoretically be
markedly delayed in onset.
Presentations
Amiodarone hydrochloride 100 mg tablets (30)
Amiodarone hydrochloride 200 mg tablets (30)
Amiodarone hydrochloride 150 mg/3 mL ampoules
Reference
Leatham EW, Holt DW, McKenna WJ. Class III antiarrhythmics in overdose: presenting
features and management principles. Drug Safety 1993; 9(6):450–462.
SPECIFIC TOXINS
3.7 AMISULPRIDE
Amisulpride overdose is associated with QT prolongation and torsades
de pointes. Ingestions of >4 g should be monitored for at least 16 hours
and until all ECG intervals are normal.
RISK ASSESSMENT
• Small overdoses (<4 g) are generally benign. 157
• Larger ingestions (>4 g) pose an increasing risk of:
— QT prolongation
— Torsades de pointes
TOXICOLOGY HANDBOOK
— Bradycardia
— Hypotension
— CNS depression.
• Children: all suspected ingestions require assessment in hospital.
Toxic mechanism
Amisulpride is an atypical antipsychotic (benzamide derivative). It acts as a dopamine
antagonist (binds to D2 and D3 receptors) with minimal affinity for serotonin, histamine
and muscarinic receptors.
Toxicokinetics
Amisulpride has an oral bioavailability of about 50% with two absorption peaks, one at 1
hour and the other at 4 hours. Peak serum concentrations may occur later than this in
overdose. It has a moderately large volume of distribution (5.8 L/kg) and limited
metabolism to inactive metabolites. Most drug is excreted unchanged via faecal and
renal routes, with an elimination half-life of about 12 hours following therapeutic doses.
TABLE 3.7.1 Dose-related risk assessment: Amisulpride

Dose Risks
<4 g Mild-to-moderate sedation and mild anticholinergic features

QT prolongation and torsades de pointes have been reported in
this dose range
>4 g Cardiotoxicity including bradycardia, hypotension, QT prolongation,

torsades de pointes and bundle branch blocks
Coma and seizures with very large ingestions
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
Large ingestions may appear mildly symptomatic for some hours,
although QT prolongation may be evident on early 12-lead ECGs.
Onset of sedation, bradycardia, hypotension and torsades de pointes
is usually delayed some hours. The time to first episode of torsades
de pointes is from 5 to 20 hours following ingestion. The latest
reported occurrence of torsades de pointes is 32 hours following
ingestion. Coma and seizures are rare but reported with large
ingestions.
INVESTIGATIONS
SPECIFIC TOXINS

• Serial ECGs
— The key investigation is the ECG. Any prolongation of the QT
is significant and mandates continuous cardiac monitoring
until normalisation (see Chapter 2.20: The 12-lead ECG in
toxicology for a discussion of QT prolongation and risk of
torsades de pointes).
158 • EUC
— Check for abnormalities in K+, Ca2+ and Mg2+ concentrations if
15
ECG abnormalities are detected.

8
TOXICOLOGY HANDBOOK
MANAGEMENT
• Amisulpride overdose is a life-threatening emergency and
managed in an area equipped for cardiorespiratory monitoring
and resuscitation.
• Clinical features that require immediate intervention include:
— Hypotension
— Coma.
• The patient who presents with established severe toxicity may
require intubation, ventilation and control of torsades de pointes
with magnesium and chemical or electrical pacing.
• Hypotension usually responds well to simple volume replacement.
• Continuous cardiac and haemodynamic monitoring with serial
12-lead ECGs for a minimum of 16 hours is mandated if the
ingested dose exceeds 4 g.
• Continue monitoring until the patient is asymptomatic and the
ECG has normalised.
Decontamination
• Oral activated charcoal is appropriate following ingestion of >4 g
within the previous 4 hours.
Antidote
• None available.
ERRNVPHGLFRVRUJ
• Patients who ingest <4 g and have a normal 12-lead ECG do not
require further observation or monitoring.
• Patients who ingest >4 g and remain asymptomatic and have a
normal ECG at 16 hours do not require further observation or
monitoring.
• Symptoms or QT prolongation mandate continued cardiac
monitoring until these abnormalities resolve. Large overdoses
require intensive care admission for advanced supportive care.
HANDY TIPS
• Following large ingestions, patients may demonstrate only mild
symptoms for several hours prior to sudden deterioration.
SPECIFIC TOXINS
• Bradycardia occurs in up to 25% of cases and is strongly
associated with a higher risk of QT prolongation and torsades de
pointes.
PITFALL
• Failure to closely examine the ECG intervals.
CONTROVERSY
• The threshold dose for risk of amisulpride-related QT prolongation 159
and torsades de pointes.
Presentations
TOXICOLOGY HANDBOOK
Amisulpride 100 mg tablets (30)
References
Isbister GK, Balit CR, MacLeod D, Duffull SB. Amisulpride overdose is frequently
associated with QT prolongation and torsades de pointes. Journal of Clinical
Pharmacology 2010; 30:391–395.
Isbister GK, Murray L, John S et al. Amisulpride deliberate self poisoning causing severe
cardiac toxicity including QT prolongation and torsades de pointes. Medical Journal
of Australia 2006; 184:354–356.
3.8 AMPHETAMINES AND OTHER

SYMPATHOMIMETICS
Amphetamines: Dexamphetamine, Methamphetamine, Methylphenidate,
3,4-methylenedioxyamphetamine (MDA),
3,4-methylenedioxymethamphetamine (MDMA, ecstasy), Cathinones,
Phenylethylamines, Piperazines
See also Chapter 2.13: Amphetamine use disorder.
Amphetamines and other sympathomimetics produce central and
peripheral sympathomimetic effects. Lethal complications include severe
hyperthermia, acute coronary syndrome, cardiac dysrhythmias, aortic
dissection and intracranial haemorrhage. Repeated use leads to long-
term neuropsychiatric sequelae.
ERRNVPHGLFRVRUJ
Multiple analogues of the sympathomimetic drugs are emerging and
available locally and via the internet. Many have hallucinogenic as well as
sympathomimetic properties. The principles of management, most
importantly supportive care and benzodiazepines, are the same.
RISK ASSESSMENT
• Small doses, particularly in non-tolerant patients, may result in
significant intoxication.
• The presence of hyperthermia, headache, impaired level of
consciousness, focal neurological signs or chest pain herald
potentially life-threatening complications and warrant aggressive
management and investigation.
• Seizures occur in up to 4% of amphetamine emergency
SPECIFIC TOXINS
presentations.
• Children: one illicit amphetamine-derivative pill may lead to
life-threatening sympathomimetic toxicity.
Toxic mechanism
Amphetamine is structurally related to ephedrine. Substitutions on the basic
amphetamine structure yield numerous derivatives with varying receptor affinities.
Amphetamines enhance catecholamine release and block reuptake. Inhibition of
monoamine oxidase also occurs. CNS and peripheral noradrenergic, dopaminergic and
160 serotonergic stimulation occurs. Long-term CNS effects occur due to neurotransmitter
16
and receptor adaptation, as well as permanent destruction of dopaminergic neuro-

0
pathways. MDMA at standard recreational doses sometimes induces the syndrome of

inappropriate antidiuretic hormone secretion (SIADH), leading to profound hyponatraemia,
TOXICOLOGY HANDBOOK
coma and convulsions.
Toxicokinetics
The amphetamines and their analogues are well absorbed following ingestion and
insufflation. They are lipid-soluble weak bases and have large volumes of distribution
(methamphetamine 3.5 L/kg). Most amphetamines undergo hepatic metabolism to form
metabolites that are excreted in the urine. Elimination half-life varies from 8 to 30 hours.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, medical
complications of abuse or psychiatric sequelae. The most frequent
presentation is agitation with sweating, tachycardia and hypertension.
Acute clinical features may persist for 24 hours and include:
• Central nervous system
— Euphoria
— Anxiety, dysphoria, agitation and aggression
— Paranoid psychosis with visual and tactile hallucinations
— Hyperthermia, rigidity and myoclonic movements
— Seizures
• Cardiovascular
— Tachycardia and hypertension
— Dysrhythmias
— Acute coronary syndrome
— Acute cardiomyopathy
— Acute pulmonary oedema
— Haemoptysis
• Peripheral sympathomimetic
— Mydriasis, sweating and tremor
ERRNVPHGLFRVRUJ
• Clinical features associated with medical complications
— Rhabdomyolysis, dehydration and renal failure
— Hyponatraemia and cerebral oedema following MDMA or
cathinone ingestion, due to temporary SIADH and increased
water ingestion
— Aortic and carotid artery dissection
— Subarachnoid and intracerebral haemorrhage
— Ischaemic colitis.
• Note: Psychotic symptoms such as paranoid ideation may
accompany acute intoxication and persist as part of a post-
amphetamine psychosis when other features of acute intoxication
have resolved.
SPECIFIC TOXINS
INVESTIGATIONS
• EUC
— Detect hyponatraemia and renal failure.
• ECG, CK and troponin
— Detect myocardial ischaemia, acute coronary syndrome and
rhabdomyolysis. 161
• Chest X-ray
— Detect aortic dissection and aspiration.
• Decreased mental status or focal neurological signs prompts
TOXICOLOGY HANDBOOK
exclusion of hyponatraemia, hypoglycaemia, aortic dissection or
intracranial haemorrhage.
• Note: Serum or urine amphetamine levels are not readily available
and do not assist acute management.
MANAGEMENT
• Amphetamine intoxication is a potentially life-threatening
emergency and patients should be managed in an area capable
of cardiorespiratory monitoring and resuscitation.
— Hypertension
— Acute coronary syndrome
— Seizures and agitated delirium
— Hyperthermia
— Hyponatraemia (MDMA, cathinones).
• Acute coronary syndrome is largely managed with standard
protocols except that beta-blockers are avoided and, as it is
frequently due to vasospasm or dissection, thrombolysis is not
usually appropriate.
• Treat tachycardia and hypertension with titrated parenteral
benzodiazepines. If hypertension is refractory to benzodiazepine
sedation consider:
— Phentolamine 1 mg IV repeated every 5 minutes
— Titrated vasodilator infusion (sodium nitroprusside, glyceryl
trinitrate).
ERRNVPHGLFRVRUJ
— Note: Beta-adrenergic blockers are contraindicated (see
Handy tips).
• Seizures are managed with IV benzodiazepines (see Chapter 2.6:
Seizures).
• Agitation is managed with titrated diazepam. Oral diazepam may
be considered in mild cases (10–20 mg diazepam PO with further
doses of 10 mg every 20 minutes until agitation controlled) but IV
diazepam should be instituted early where agitation is moderate
or severe. Give diazepam 2.5–5 mg IV. Further doses of 5–10 mg
IV every 5–10 minutes to a maximum dose of 60 mg may be
required (see Chapter 2.7: Delirium and agitation). Second-line
drugs in resistant cases include droperidol 2.5–10 mg IV or
olanzapine 10 mg IM.
• Hyperthermia:
SPECIFIC TOXINS
— Temperature >38.5°C is an indication for continuous core-

temperature monitoring, benzodiazepine sedation and fluid
resuscitation.
— Temperature >39.5°C requires rapid external cooling to
prevent multiple organ failure and neurological injury.
Paralysis, intubation and ventilation may be required.
• Hyponatraemia:
— Immediate correction with hypertonic saline (sodium chloride
162 3%) is indicated if profound (serum Na+ <120 mmol/L) and
associated with altered mental status or seizures. Give
16
2
hypertonic saline (3% sodium chloride) 4 mL/kg over 30

minutes and repeat serum sodium. Further doses should be
TOXICOLOGY HANDBOOK
given to achieve a serum Na+ >120 mmol/L until resolution of

SIADH manifests by diuresis and spontaneous correction of
hyponatraemia (this usually occurs within 24 hours).
Decontamination
• Amphetamines are rapidly absorbed and associated with an
increased risk of seizures and delirium; therefore, activated
charcoal is not advised.
Antidotes
• None available.
• Children with potential ingestions should be observed in hospital
for 4 hours. If they do not develop symptoms during that period
they may then be safely discharged.
• Patients whose intoxication is adequately controlled with
benzodiazepine sedation and have a normal blood
pressure and 12-lead ECG may be managed supportively
in a ward environment. They may be discharged when
clinically well.
• Patients with significant alteration of conscious state,
hyperthermia or ongoing chest pain are admitted to a high-
dependency or intensive care unit.
ERRNVPHGLFRVRUJ
HANDY TIPS
• Early control of agitation with adequate doses of IV
benzodiazepines calms the patient and improves tachycardia,
hypertension and hyperthermia.
• Ongoing chest pain or headache requires further investigation.
• CT brain should be performed prior to anticoagulation or
angiography if headache is a feature.
• Administration of beta-adrenergic blockers is contraindicated in
the acute management of amphetamine intoxication as it leads to
unopposed alpha stimulation and vasoconstriction.
PITFALLS
• Failure to adequately sedate the agitated patient.
SPECIFIC TOXINS
• Failure to recognise and treat hyperthermia.
• Failure to detect and treat hyponatraemia in a patient presenting
with altered mental status or seizures following MDMA or
cathinone use – permanent neurological injury can result.
CONTROVERSY
• The role of antipsychotics in acute amphetamine intoxication.
They are frequently effective in the treatment of persistent
psychosis but have theoretical drawbacks in acute intoxication: 163
anticholinergic side effects and lowered seizure threshold.
Presentations
TOXICOLOGY HANDBOOK
Prescription medications
Dexamphetamine 5 mg tablets (100)
Methylphenidate 10 mg tablets (100)
Methylphenidate 20 mg capsules (30)
Methylphenidate 30 mg capsules (30)
Methylphenidate 40 mg capsules (30)
Methylphenidate 18 mg extended-release tablets (30)
Illicit amphetamine-derivative pills
Methamphetamine: ice, speed, P
3,4-methylenedioxymethamphetamine (MDMA): ecstasy, XTC
3,4-methylenedioxyamphetamine (MDA): love drug
Cathinones
Khat (Catha edulis)
Mephedrone (4-methylmethcathinone): Bath salts, Plant food
Methylenedioxypyrovalerone (MDPV)
3,4-Methylenedioxy-a-Dimethylecathinone pyrrolindinopropiophenone (MDPPP)
Methcathinone
Ethcathinone
Ethylone
Pyrovalerone
Naphyrone
Methylone
Butylone
3-Fluoromethcathinone
4-Fluoromethcathinone (flephedrone)
Brephedrone
a-Pyrrolidinovalerophenone
ERRNVPHGLFRVRUJ
Phenylethylamines
2C-B 4-Bromo-2,5-dimethoxyphenethylamine
2C-B-Fly 8-Bromo-2,3,6,7-benzo-dihydro-difuran-ethylamine
2C-C 4-Chloro-2,5-dimethoxyphenethylamine
2C-D 4-Methyl-2,5-dimethoxyphenethylamine
2C-E 4-Ethyl-2,5-dimethoxyphenethylamine
2C-F 4-Fluoro-2,5-dimethoxyphenethylamine
2C-G 3,4-Dimethyl-2,5-dimethoxyphenethylamine
2C-I 4-Iodo-2,5-dimethoxyphenethylamine
2C-I-Fly 8-Iodo-2,3,6,7-benzo-dihydro-difuran-ethylamine
2C-N 4-Nitro-2,5-dimethoxyphenethylamine
2C-P 4-Propyl-2,5-dimethoxyphenethylamine
2C-SE 4-Methylseleno-2,5-dimethoxyphenethylamine
2C-T 4-Methylthio-2,5-dimethoxyphenethylamine
2C-T-2 4-Ethylthio-2,5-dimethoxy-b-phenethylamine
SPECIFIC TOXINS
Piperazines
1-benzylpiperazine (BZP)
1-(3-trifluoromethylphenyl)piperazine (TFMPP)
1-methyl-4-benzylpiperazine
1-(3-chlorophenyl)piperazine
1-(2-methoxy-phenyl)piperazine
References
Gray SD, Fatovich DM, McCoubrie DL et al. Amphetamine related presentations to an
inner city tertiary emergency department: a prospective evaluation. Medical Journal
164 of Australia 2007; 186(7):336–339.
16
Jenner L, Spain D, Whyte I et al. Management of patients with psychostimulant toxicity:

4
guidelines for emergency departments. Canberra: Australian Government Department

of Health and Ageing; May 2006. Available online at: http://www.health.gov.au/
TOXICOLOGY HANDBOOK
internet/drugstrategy/publishing.nsf/Content/publications-psychostimulant
-emergency.
Nelson ME, Bryant SM, Aks SE. Emerging drugs of abuse. Emergency Medicine Clinics
of North America 2014; 32:1–28.
3.9 ANGIOTENSIN-CONVERTING ENZYME INHIBITORS

Captopril, Enalapril, Fosinopril, Lisinopril, Perindopril, Quinapril, Ramipril,
Trandolapril
Overdose with angiotensin-converting enzyme (ACE) inhibitors is
relatively benign. The principal toxic effect is mild-to-moderate
hypotension usually responsive to fluid therapy alone.
RISK ASSESSMENT
• Overdose with these agents is generally benign, irrespective of
the dose ingested.
• Mild hypotension can occur. It is usually apparent within 2 hours
of ingestion, may last several hours and is easily managed with
intravenous fluid administration.
• Children: ingestion of up to two times the defined daily dose
(DDD) for adults does not produce symptoms and does not
require hospital evaluation.
Toxic mechanism
Angiotensin-converting enzyme inhibitors bind to and inactivate angiotensin-converting
enzyme (ACE) in a reversible manner. This prevents conversion of angiotensin I to
ERRNVPHGLFRVRUJ
angiotensin II, a powerful vasopressor. Angiotensin II also has a number of endocrine
effects and its inhibition leads to a reduction in circulating aldosterone, which can lead to
hyperkalaemia.
Toxicokinetics
These agents are all rapidly and well absorbed orally with peak levels occurring within
1–2 hours. Many agents are pro-drugs and require hepatic conversion to become active.
Elimination is renal.
CLINICAL FEATURES
Patients are usually asymptomatic. The principal clinical feature is mild
hypotension. If this occurs, it will manifest within 2 hours of the ingestion and
may last several hours. The duration of hypotension will relate to both the
preparation and the dose ingested.
SPECIFIC TOXINS
INVESTIGATIONS
• EUC
— Mild hyperkalaemia and renal impairment may be observed.
MANAGEMENT 165
• Resuscitation is rarely required and management is entirely
supportive.
TOXICOLOGY HANDBOOK
• Patients presenting with significant hypotension usually respond
to a fluid bolus of 10–20 mL/kg of intravenous crystalloid
solution.
• Ongoing fluid administration may sometimes be necessary.
• Standard observations are sufficient.
Decontamination
• Oral activated charcoal may be given to the patient who presents
within 1 hour of ingestion but is unlikely to significantly alter the
clinical course.
Antidotes
• None available.
• The patient who remains asymptomatic with normal blood
pressure at 4 hours following ingestion does not require further
medical care or observation.
• The symptomatic or hypotensive patient is admitted to a
non-monitored bed for ongoing supportive care until clinical
features of poisoning resolve.
CONTROVERSY
• Both naloxone and angiotensin have been advocated as antidotes
for hypotension following ACE inhibitor overdose. A trial of these
ERRNVPHGLFRVRUJ
agents does not appear justified given the benign and reversible
nature of the hypotension.
Presentations
Captopril 12.5 mg tablets (90) Perindopril erbumine 4 mg tablets (30)
Captopril 25 mg tablets (90) Perindopril erbumine 8 mg tablets (30)
Captopril 50 mg tablets (90) Perindopril erbumine 4 mg/indapamide
Enalapril maleate 5 mg tablets (30) hemihydrate 1.25 mg tablets (30)
Enalapril maleate 10 mg tablets (30) Quinapril hydrochloride 5 mg tablets (30)
Enalapril maleate 20 mg tablets (30) Quinapril hydrochloride 10 mg tablets (30)
Enalapril maleate 20 mg/ Quinapril hydrochloride 20 mg tablets (30)
hydrochlorothiazide 6 mg tablets (30) Ramipril 1.25 mg tablets (30)
Fosinopril sodium 10 mg tablets (30) Ramipril 2.5 mg tablets (30)
Fosinopril sodium 20 mg tablets (30) Ramipril 5 mg tablets (30)
Fosinopril sodium 10 mg/ Ramipril 10 mg tablets (30)
SPECIFIC TOXINS
hydrochlorothiazide 12.5 mg Trandolapril 0.5 mg tablets (28)

tablets (30) Trandolapril 1 mg tablets (28)
Fosinopril sodium 20 mg/ Trandolapril 2 mg tablets (28)
hydrochlorothiazide 12.5 mg Trandolapril 4 mg tablets (28)
tablets (30) Trandolapril 2 mg/verapamil hydrochloride
Lisinopril dihydrate 5 mg tablets (30) 180 mg sustained-release tablets (28)
Lisinopril dihydrate 10 mg tablets (30) Trandolapril 4 mg/verapamil hydrochloride
Lisinopril dihydrate 20 mg tablets (30) 240 mg sustained-release tablets (28)
Perindopril erbumine 2 mg tablets (30)
166
References
16
Balit CR, Gilmore S P, Isbister GK. Unintentional paediatric ingestions of angiotensin

6
converting enzyme inhibitors and angiotensin II receptor antagonists. Journal of

TOXICOLOGY HANDBOOK
Paediatrics and Child Health 2007; 43(10):686–688.

Christie GA, Lucas C, Bateman DN et al. Redefining the ACE-inhibitor dose–response
relationship: substantial blood pressure lowering after massive doses. European
Journal of Clinical Pharmacology 2006; 62(12):989–993.
Varughese A, Taylor AA, Nelson EB. Consequences of angiotensin-converting enzyme
inhibitor overdose. American Journal of Hypertension 1989; 2:355–357.
3.10 ANTICOAGULANT RODENTICIDES

Brodifacoum, Bromadiolone, Chlorophacinone, Difenacoum,
Diphacinone, Flocoumafen
Long-acting anticoagulant rodenticides or ‘superwarfarins’ were
developed to counter rodent resistance to warfarin. Single unintentional
paediatric ingestions are non-toxic. In contrast, massive or repeated
dosing leads to profound and prolonged (weeks to months)
anticoagulation. Warfarin is discussed in Chapter 3.80: Warfarin.
RISK ASSESSMENT
• Single accidental ingestion does not cause significant
anticoagulation.
• Massive single ingestion of >0.1 mg/kg of brodifacoum will cause
anticoagulation but this equates to 2 g/kg of 0.005% bait or 3 ×
50-g pellet packs in a 75-kg adult.
• Anticoagulation is usually associated with repeated ingestion. In
this scenario, severe, prolonged (weeks to months) anticoagulation
requiring massive doses of vitamin K is anticipated.
ERRNVPHGLFRVRUJ
• Children: it is estimated that a young child needs to ingest >30 g
of a 0.005% preparation as a single dose to cause significant
anticoagulation. This has never been reported.
Toxic mechanism
These agents inhibit hepatic vitamin K-dependent production of clotting factors II, VII, IX
and X in the same way as warfarin. Several mechanisms confer increased potency and
prolonged duration of action: greater affinity for vitamin K1-2,3-epoxide reductase,
disruption of vitamin K cycle at several sites and hepatic accumulation. These agents
have prolonged elimination half-lives.
Toxicokinetics
These agents are completely absorbed following oral administration. They are highly lipid
soluble and have large volumes of distribution. They are concentrated in the liver.
Superwarfarins undergo hepatic metabolism and enterohepatic recirculation and have
SPECIFIC TOXINS
very prolonged elimination phases of weeks to months.
CLINICAL FEATURES
• Patients are usually asymptomatic.
• Severe coagulopathy manifests as bruising, petechial or purpural
rashes, gingival bleeding, epistaxis or haematuria.
• Following acute single ingestions, coagulopathy may not be
evident for 12 hours, and is frequently delayed 24–48 hours. Peak
effects occur at 72–96 hours. 167
INVESTIGATIONS
TOXICOLOGY HANDBOOK
• INR
— In patients who are not anticoagulated, INR will be normal
during the first 6–12 hours after deliberate overdose.
Following massive overdose, perform serial INRs every 12
hours for 48 hours to rule out toxicity. Vitamin K must be
withheld until anticoagulation is documented. Normal INR at
48 hours excludes toxic ingestion.
— Following repeated ingestion over several days, INR is
abnormal at presentation. Vitamin K therapy may commence
immediately. Outpatient INR estimations are required to
monitor therapy.
• Superwarfarin levels
— Useful to confirm diagnosis in cases where paediatric
non-accidental injury or occult poisoning is suspected.
— Useful in determining when it is safe to withdraw vitamin K
therapy.
MANAGEMENT
• In patients with evidence of haemorrhage, attention to airway,
breathing and circulation are paramount. These priorities can
usually be managed along conventional lines, as outlined in
Chapter 1.2: Resuscitation.
ERRNVPHGLFRVRUJ
• If there is active uncontrolled haemorrhage, administer fresh
frozen plasma (10–15 mL/kg), Prothrombinex-HT (25–50 IU/kg)
and vitamin K 10 mg IV.
Decontamination
• Activated charcoal is not indicated following accidental
ingestions.
• Following massive single acute deliberate self-poisoning,
administer 50 g activated charcoal to cooperative patients who
are able to drink it themselves and present within 12 hours of
ingestion.
SPECIFIC TOXINS
Antidotes
• Vitamin K (phytomenadione) is indicated where there is
documented anticoagulation from repeated deliberate ingestion or
following acute deliberate self-poisoning. Prophylactic vitamin K is
contraindicated. In patients with proven anticoagulation, vitamin K
is titrated to achieve safe INR levels (<4). Very large daily doses of
168 oral vitamin K are required for weeks or months. Initial daily dose
is variable and determined under close medical supervision with
16
8
repeated INR estimations. See antidote Chapter 4.29: Vitamin K

for details.
TOXICOLOGY HANDBOOK

• Minor unintentional ingestions by adults or children do not require
hospital observation or investigation.
• Referral for an INR is indicated where there is suspicion of
repeated ingestion or abnormal bleeding. A normal INR 48 hours
after the last ingestion excludes toxicity.
• Following massive single ingestions, INR is monitored for 48
hours. A normal INR at 48 hours excludes toxicity and the patient
does not require further medical monitoring.
• Established anticoagulation requires hospital admission for
stabilisation on high-dose oral vitamin K. Prolonged supervision
of INRs and compliance with vitamin K therapy is essential and
arranged prior to discharge in consultation with mental health
services.
PITFALL
• Empiric vitamin K therapy following an acute ingestion masks
subsequent toxicity, delays diagnosis and prolongs the need for
medical supervision.
Presentations
Pellets, wax blocks, paste and liquid concentrate. Often coloured blue, green or red and
may contain a bittering agent.
Typical concentration is 0.005% (5 mg/100 g).
Pellet packs are typically 50 g (i.e. contain 2.5 mg brodifacoum).
Concentrates may be up to 0.25% (250 mg/100 g).
ERRNVPHGLFRVRUJ
References
Gunja N, Coggins A, Bidny S. Management of intentional superwarfarin poisoning with
long-term vitamin K and brodifacoum levels. Clinical Toxicology 2011; 49:385–390.
Ingels M, Lai C, Tai W et al. A prospective study of acute, unintentional, pediatric
superwarfarin ingestions managed without decontamination. Annals of Emergency
Medicine 2002; 40(1):73–78.
Shepherd G, Klein-Schwartz W, Anderson BD. Acute unintentional pediatric brodifacoum
ingestions. Pediatric Emergency Care 2002; 18(3):174–178.
Watt BE, Proudfoot AT, Bradberry SM et al. Anticoagulant rodenticides. Toxicological
Reviews 2005; 24(4):259–269.
3.11 ANTICONVULSANTS: NEWER AGENTS
SPECIFIC TOXINS
Gabapentin, Lamotrigine, Levetiracetam, Oxcarbazepine, Pregabalin,
Tiagabine, Topiramate, Vigabatrin
The newer anticonvulsants are generally much less toxic in overdose
than the older agents – phenobarbitone (see Chapter 3.16: Barbiturates),
carbamazepine (see Chapter 3.24: Carbamazepine), phenytoin (see
Chapter 3.65: Phenytoin) and valproic acid (see Chapter 3.78: Valproic
acid (sodium valproate)). Sedation and non-specific neurological
symptoms may occur. Treatment is supportive and a favourable outcome 169
can be anticipated.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
• Most overdoses with these agents produce mild and transient
CNS symptoms only.
• Symptoms usually appear within 2 hours and resolve within
24 hours.
• Coma and seizures can occur but are rare.
• Children: unintentional paediatric ingestion is benign and referral
to hospital is only indicated if symptoms develop.
Toxic mechanism
Most of these agents exert an anticonvulsant effect by potentiating gamma-amino
butyric acid (GABA) neurotransmission – either by enhancing GABA release or inhibiting
GABA reuptake at the synapse. Lamotrigine and topiramate also have effects on
voltage-dependent Na+ channels and topiramate inhibits carbonic anhydrase. Pregabalin
decreases release of excitatory neurotransmitters, especially glutamate, by blockade of
calcium channels.
Toxicokinetics
All agents are well absorbed orally, with linear kinetics. Most undergo hepatic
metabolism to inactive metabolites, and are excreted renally. Levetiracetam, pregabalin
and topiramate are primarily excreted unchanged in the urine. Absorption of gabapentin
from the GI tract is saturable at higher doses and this may act to limit toxicity following
overdose.
CLINICAL FEATURES
• Gabapentin overdose
— Nausea, vomiting, tachycardia, hypotension, drowsiness
— These clinical features, if present at all, are mild and resolve
within 10 hours.
ERRNVPHGLFRVRUJ
• Lamotrigine overdose
— Ataxia, nystagmus, slurred speech, drowsiness, transient
intraventricular conduction delay (rare) and seizures (rare)
— Clinical features are of rapid onset and resolve within 24–48
hours.
• Levetiracetam overdose
— Agitation, depressed level of consciousness, coma, respiratory
depression
• Oxcarbazepine overdose
— Sedation, usually mild even after massive overdose
• Pregabalin overdose
— Drowsiness only
• Tiagabine overdose
— Sedation, coma, respiratory depression and seizures
SPECIFIC TOXINS
• Topiramate overdose
— Ataxia, sedation, coma, seizures, hypotension and metabolic
acidosis
— The CNS effects are of rapid onset, usually within hours, and
resolve within 24 hours.
— Non-anion gap metabolic acidosis is secondary to carbonic
anhydrase inhibition and may persist for up to 7 days. It is of
little clinical significance.
170 • Vigabatrin overdose
— Drowsiness and delirium
17
0
TOXICOLOGY HANDBOOK
INVESTIGATIONS
• EUC, acid–base status for topiramate
• Specific drug levels are neither readily available nor clinically
useful.
MANAGEMENT
— Coma – intubation and ventilation are indicated
— Respiratory depression – intubation and ventilation are
indicated
— Seizures – control with titrated doses of benzodiazepines as
described in Chapter 2.6: Seizures.
Decontamination
• In view of the relatively minor toxicity associated with most
of these agents, and their rapid absorption from the
gastrointestinal tract, routine gastrointestinal decontamination
is not indicated.
ERRNVPHGLFRVRUJ
• A dose of activated charcoal 50 g (1 g/kg in children) may be
given via a nasogastric tube to the patient with coma or seizures
after the airway is secured with endotracheal intubation.
Antidotes
• None available.
• Children may be observed at home following suspected
unintentional ingestion of these agents. They need only be
referred for hospital assessment and observation if symptoms
SPECIFIC TOXINS
develop.
• Patients who remain asymptomatic 6 hours post-ingestion are
medically fit for discharge. Those who develop symptoms are
admitted for further observation and supportive care until those
symptoms resolve, usually within 24 hours.
HANDY TIPS
• Although coma is reported with very large doses of some of the
newer anticonvulsants, other toxicological causes should be 171
considered in these cases. In particular, it is essential to exclude
coma from carbamazepine, valproic acid or barbiturate overdose,
with drug levels if necessary.
TOXICOLOGY HANDBOOK
• Oxcarbazepine, although structurally similar to carbamazepine, is
much less toxic in overdose.
Presentations
Gabapentin 100 mg capsules (100) Oxcarbazepine 60 mg/1 mL oral
Gabapentin 300 mg capsules (100) suspension (250 mL)
Gabapentin 400 mg capsules (100) Pregabalin 25 mg capsules (56)
Gabapentin 600 mg tablets (100) Pregabalin 75 mg capsules (56)
Gabapentin 800 mg tablets (100) Pregabalin 150 mg capsules (56)
Lamotrigine 5 mg tablets (56) Pregabalin 300 mg capsules (56)
Lamotrigine 25 mg tablets (56) Tiagabine hydrochloride 5 mg tablets (50)
Lamotrigine 200 mg tablets (56) Topiramate 25 mg tablets (60)
Levetiracetam 250 mg tablets (60) Topiramate 50 mg tablets (60)
Levetiracetam 100 mg/1 mL oral solution Topiramate 15 mg sprinkle capsules (60)
(300 mL) Topiramate 25 mg sprinkle capsules (60)
Levetiracetam 500 mg/5 mL vials Topiramate 50 mg sprinkle capsules (60)
Oxcarbazepine 150 mg tablets (100) Vigabatrin 500 mg (100)
Oxcarbazepine 300 mg tablets (100) Vigabatrin 500 mg sachets (60)
Oxcarbazepine 600 mg tablets (100)
References
Fischer JH, Barr AN, Rogers SL et al. Lack of serious toxicity following gabapentin
overdose. Neurology 1994; 44(5):982–983.
Klein-Schwartz W, Shepherd JG, Gorman S et al. Characterization of gabapentin
overdose using a poison center case series. Journal of Toxicology–Clinical
Toxicology 2003; 41(1):11–15.
ERRNVPHGLFRVRUJ
Lofton AL, Klein-Schwartz W. Evaluation of lamotrigine toxicity reported to poison
centers. Annals of Pharmacotherapy 2004; 38:1811–1815.
Traub JS, Howland MA, Hoffman RS et al. Acute topiramate toxicity. Journal of
Wade J F, Dang CV, Nelson L et al. Emergent complications of the newer
anticonvulsants. Journal of Emergency Medicine 2010; 38(2):231–237.
Wisniewski M, Lukasek-Glebocka M, Anand JS. Acute topiramate overdose—clinical
manifestations. Clinical Toxicology 2009; 47:317–320.
3.12 ANTIHISTAMINES (non-sedating)

Cetirizine, Desloratadine, Fexofenadine, Levocetirizine, Loratadine
SPECIFIC TOXINS
See also Chapter 3.13: Antihistamines (sedating).

The non-sedating antihistamines produce mild CNS depression in
overdose. They are notable for their association with QT prolongation in
therapeutic and supratherapeutic doses, although this association is less
marked with the newer currently available agents.
RISK ASSESSMENT
• Mild sedation or anticholinergic effects are anticipated following
172 overdose.
• QT prolongation following overdose of currently available
17
agents is reported but rare. It is more likely following a large

2
ingestion or where there is co-ingestion of another pro-

TOXICOLOGY HANDBOOK
dysrhythmic agent.
• Children: ingestion of one to three tablets may be observed at
home. Refer to hospital for supportive care if significant
drowsiness or anticholinergic symptoms develop.
Toxic mechanism
Non-sedating antihistamines are mildly lipophilic and less able to cross the blood–brain
barrier than sedating antihistamines. They are selective, competitive reversible inhibitors
of peripheral H1 receptors. Compared to sedating antihistamines, they have lower affinity
for central H1, muscarinic (M1), α1-adrenergic and serotonergic (5-HT) receptors. In
overdose, selectivity may be lost and some sedation, anticholinergic effects and
hypotension may be seen. QT interval prolongation is secondary to cardiac potassium
channel blockade.
Toxicokinetics
Non-sedating antihistamines are well absorbed, reach peak effects in 1–3 hours and
have volumes of distribution of less than 1.5 L/kg. Hepatic metabolism is minor and
half-lives are variable, ranging from 8 to 24 hours.
CLINICAL FEATURES
• Minor sedation, nausea and ataxia
• Mild anticholinergic symptoms
• Symptoms develop within 4–6 hours of ingestion and resolve
within 12–24 hours.
INVESTIGATIONS
ERRNVPHGLFRVRUJ
• Serial 12-lead ECGs
• Perform ECGs every 4 hours until there is clear evidence of
clinical improvement.
MANAGEMENT
• Resuscitation is rarely required but the patient should be
monitored initially and for 12 hours if symptomatic because of the
small risk of QT prolongation.
• Manage anticholinergic delirium as outlined in Chapter 2.9:
SPECIFIC TOXINS
Anticholinergic syndrome.
• Severe QT prolongation with torsades de pointes is largely a
theoretical risk. Treatment should it occur includes correction of
hypoxia, hypokalaemia, hypomagnesaemia and hypocalcaemia. If
the heart rate is less than 100 beats/minute, consider an
isoprenaline infusion IV (1–10 microgram/minute or 0.05–2.0
microgram/kg/minute in children) or overdrive pacing to maintain
heart rate at 100–120 beats/minute.
Decontamination 173
TOXICOLOGY HANDBOOK
Antidotes
• Physostigmine administration is considered in patients with severe
anticholinergic delirium not controlled with benzodiazepines (see
Chapter 4.21: Physostigmine).

• Symptomatic patients have continuous cardiac monitoring and
12-lead ECGs every 4 hours until there is clear evidence of
clinical improvement.
• The patient is fit for medical discharge when clinically well,
ambulant, passing urine, eating and drinking.
• Patients with significant agitation or cardiac dysrhythmias require
admission to a high-dependency or intensive care unit.
HANDY TIP
• Most ingestions are benign and have a good outcome with
minimal supportive care.
PITFALL
• Failing to recognise the potential for QT prolongation in
overdose.
CONTROVERSY
• The use of prophylactic magnesium in the setting of QT
prolongation.
ERRNVPHGLFRVRUJ
Presentations
Cetirizine hydrochloride 10 mg tablets (7, Fexofenadine hydrochloride 180 mg
10, 30) tablets (10, 20, 30, 50)
Cetirizine hydrochloride 1 mg/1 mL oral Fexofenadine hydrochloride 60 mg/
solution (75, 200 mL) pseudoephedrine 120 mg tablets (10)
Cetirizine hydrochloride 10 mg/1 mL oral Levocetirizine 5 mg tablets (10, 30)
drops (20 mL) Loratadine 10 mg tablets (10, 30, 50)
Desloratadine 5 mg tablets (7, 28) Loratadine 1 mg/1 mL syrup (100 mL,
Fexofenadine hydrochloride 30 mg tablets 150 mL, 200 mL)
(10, 20) Loratadine 5 mg/pseudoephedrine 120 mg
Fexofenadine hydrochloride 60 mg tablets modified-release tablets (6)
(10, 20)
Fexofenadine hydrochloride 120 mg
tablets (10, 20, 30, 50)
SPECIFIC TOXINS
References
Hoffman RJ, de Souza I, Stetz JE. Prolonged QT segment and syncope with
loratadine use (abstract). Journal of Toxicology – Clinical Toxicology 2001;
39:505.
Pinto YM, Van Gelder IC, Heeringa M et al. QT lengthening and life-threatening
arrhythmias associated with fexofenadine. Lancet 1999; 353:980.
174 3.13 ANTIHISTAMINES (sedating)

17
4
Brompheniramine, Chlorpheniramine, Cyproheptadine,

Dexchlorpheniramine, Dimenhydrinate, Diphenhydramine, Doxylamine,
TOXICOLOGY HANDBOOK
Pheniramine, Promethazine
See also Chapter 3.12: Antihistamines (non-sedating).
Overdose is characterised by dose-dependent sedation and
anticholinergic effects. Cardiovascular toxicity is associated with
massive ingestions.
RISK ASSESSMENT
• Dose-dependent sedation, anticholinergic effects and orthostatic
hypotension occur.
• All agents lower seizure threshold, but seizures are infrequent.
• Massive overdose may result in cardiac conduction abnormalities
(increased QRS or QT intervals) and hypotension requiring
inotropes.
• Children: ingestion is associated with drowsiness and
anticholinergic delirium.
Toxic mechanism
Antihistamines act by competitive inhibition of histamine (H1) receptors. Side effects and
toxicity are due to antagonism at muscarinic (M1), α1-adrenergic and serotonergic (5-HT)
receptors. Some agents lower seizure threshold but mechanisms are unclear. Cardiac
sodium and potassium channel blockade is reported in massive ingestions.
Toxicokinetics
Antihistamines are well absorbed after ingestion, reaching peak levels in 2–3 hours. They
are lipid soluble, have large volumes of distribution (>4 L/kg) and are metabolised in the
liver. Half-lives are variable and range between 6 and 18 hours.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
• CNS depression.
• Anticholinergic syndrome including delirium (see Chapter 2.9:
Anticholinergic syndrome).
• Seizures, hyperthermia and rhabdomyolysis are rare.
• Significant hypotension requiring inotropic support and cardiac
conduction abnormalities secondary to fast sodium channel
blockade (e.g. diphenhydramine) occur rarely after massive
overdose.
INVESTIGATIONS
SPECIFIC TOXINS
— An ECG should be performed on presentation and at 6 hours
post-ingestion to detect QRS or QT interval prolongation.
Further serial ECGs are only necessary if an abnormality is
noted.
MANAGEMENT 175
• Resuscitation is rarely required but the patient should be
monitored initially and for 6 hours if symptomatic because of the
TOXICOLOGY HANDBOOK
risk of QRS or QT prolongation.
• Manage anticholinergic delirium as outlined in Chapter 2.9:
Anticholinergic syndrome.
• Manage seizures as outlined in Chapter 2.6: Seizures.
• Hypotension usually responds to fluid administration. If not, an
α1-adrenergic agonist (noradrenaline) is second-line therapy.
• In the rare event of QRS prolongation complicated by ventricular
dysrhythmias, intubate, hyperventilate and give IV bolus sodium
bicarbonate, as outlined in Chapter 4.25: Sodium bicarbonate.
Decontamination
• Activated charcoal is not routinely indicated because the onset of
sedation occurs in the first few hours and simple supportive care
ensures a good outcome.
Antidotes
• Physostigmine administration is considered in patients with severe
anticholinergic delirium not controlled with benzodiazepines (see
Chapter 4.21: Physostigmine).

• Patients who remain asymptomatic and have a normal 12-lead ECG
at 6 hours may be discharged. Discharge should not occur at night.
ERRNVPHGLFRVRUJ
• Patients with mild sedation or anticholinergic features but a
normal 12-lead ECG at 6 hours may be managed supportively in
a ward environment. They are fit for medical discharge when well,
ambulant, passing urine, eating and drinking.
• Patients with significant agitation or delirium, and those requiring
intubation, require admission to a high-dependency or intensive
care unit.
• Ongoing cardiac monitoring is reserved for patients with abnormal
ECGs, until changes resolve.
HANDY TIP
• Antihistamines may be abused for their anticholinergic properties.
SPECIFIC TOXINS
PITFALLS
• Failure to recognise anticholinergic delirium because of
concomitant sedative effects.
• Failure to detect and relieve urinary retention. This exacerbates
agitation and prevents control with benzodiazepine sedation.
CONTROVERSY
• Role of physostigmine in the management of antihistamine-
176 induced anticholinergic delirium.
17
Presentations
6
Alkylamines
TOXICOLOGY HANDBOOK
Brompheniramine 2 mg/5 mL in decongestant elixirs

Chlorpheniramine 0.5–6 mg/tablet or 5 mL of elixir in cold and flu formulations
Dexchlorpheniramine maleate 2 mg modified-release tablets (20, 40)
Dexchlorpheniramine maleate 6 mg modified-release tablets (20, 40)
Dexchlorpheniramine 2.5 mg/1 mL syrup (100 mL)
Ethanolamines
Dimenhydrinate 50 mg/hyoscine hydrobromide 0.2 mg/caffeine 20 mg tablets (10)
Diphenhydramine hydrochloride 50 mg capsules (10)
Diphenhydramine hydrochloride 50 mg tablets (10)
Diphenhydramine 2.5 mg/mL in cough syrup formulations
Doxylamine succinate 25 mg capsules (20)
Doxylamine succinate 6.25 mg per tablet in cold and flu preparations
Doxylamine 5–6.25 mg per tablet with paracetamol–codeine combination analgesics
Phenothiazines
Pheniramine maleate 43.5 mg tablets (10, 50)
Promethazine hydrochloride 10 mg tablets (50)
Promethazine hydrochloride 25 mg tablets (50)
Promethazine hydrochloride 1 mg/1 mL elixir (100 mL)
Promethazine hydrochloride 25 mg/1 mL ampoules
Promethazine hydrochloride 50 mg/2 mL ampoules
Promethazine hydrochloride in cold and flu formulations and analgesics (e.g. Pain Stop)
Trimeprazine 7.5 mg/5 mL syrup (100 mL)
Trimeprazine 6 mg/1 mL syrup (100 mL)
Others
Cyproheptadine tablets 4 mg (50, 100)
References
Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and
benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency
Medicine 2000; 35(4):374–381.
ERRNVPHGLFRVRUJ
Clark RF, Vance MV. Massive diphenhydramine poisoning resulting in a wide-complex
tachycardia: successful treatment with sodium bicarbonate. Annals of Emergency
Medicine 1992; 21:318–321.
3.14 ARSENIC
Arsenic is a metal found in elemental, inorganic and organic forms. The
inorganic and organic forms exist as trivalent (arsenite) and pentavalent
(arsenate) forms. Most commercially available arsenic-containing
products are produced from arsenic trioxide, one of the more toxic
trivalent inorganic compounds. Acute ingestion, usually in the context of
deliberate self-poisoning, is followed by severe gastroenteritis with a
characteristic sequential life-threatening multiple organ failure. Subacute
SPECIFIC TOXINS
exposures occur from industrial accidents, food contamination and
ingestion of arsenic-containing herbal medicines. Chronic intoxication
usually follows long-term drinking of contaminated artesian water. The
organic arsenoids found in seafood are non-toxic.
RISK ASSESSMENT
• Acute or subacute ingestion of inorganic arsenic leads to a
dose-dependent sequential pattern of multiple organ failure:
— Ingestion of >1 mg/kg is potentially lethal 177
— Ingestion of <0.05 mg/kg may cause mild self-limiting
gastrointestinal symptoms but does not cause systemic
toxicity.
TOXICOLOGY HANDBOOK
• Chronic arsenic intoxication usually occurs secondary to long-
term (>10 years) drinking of contaminated artesian water.
• Children: any ingestion of arsenic insecticide should be regarded
as potentially lethal.
Toxic mechanism
Arsenic binds to numerous cellular enzymes, interferes with cellular respiration and
inhibits DNA replication and repair. It binds to sulfhydryl (SH−) groups and substitutes
for phosphate in ATP. It produces reactive oxygen intermediates causing lipid
peroxidation.
Toxicokinetics
Absorption occurs via dermal, respiratory and gastrointestinal routes. Elimination half-life
is 3–5 days following acute ingestion. Arsenic initially distributes to kidneys and liver.
Following chronic ingestion, arsenic is distributed to liver, kidneys, lungs, nervous
system, spleen, hair and nails. Arsenic undergoes hepatic methylation and the
metabolites are excreted in the urine. A small amount of inorganic arsenic is excreted in
the urine unchanged. The organic arsenoids found in seafood are excreted unchanged.
CLINICAL FEATURES
Acute toxicity
• Following large ingestions there is rapid onset of severe watery
diarrhoea (‘choleroid’ or ‘rice water diarrhoea’), vomiting and
abdominal pain.
• Gastrointestinal haemorrhage may occur.
• Encephalopathy, seizures and cardiovascular collapse develop
within hours.
• Hypersalivation is characteristic, as is a garlic odour.
ERRNVPHGLFRVRUJ
• Acute cardiomyopathy, ECG changes (prolonged QT) and cardiac
dysrhythmias are described.
• Acute adult respiratory distress syndrome, renal failure and
hepatic injury follow.
• Bone marrow depression develops within 24–72 hours in
survivors, reaching a nadir in 2–3 weeks.
• Alopecia occurs in survivors of the initial phase.
• Peripheral neuropathy may develop with a delay of 1–3 weeks. It
is an ascending predominantly motor neuropathy, may mimic
Guillain-Barré syndrome and may progress to respiratory failure.
Subacute toxicity
• Initially manifests with gastrointestinal symptoms, leucopenia,
deranged liver function and haematuria.
SPECIFIC TOXINS
• Peripheral neuropathy develops after several weeks.

Chronic toxicity
• Insidious onset over years of a multi-system disorder manifested
by constitutional symptoms, cutaneous lesions (hyperkeratosis of
palms and soles, hyperpigmentation), nail changes (Mees’ lines),
painful peripheral neuropathy (glove-stocking type distribution),
and malignancies of the skin or bladder.
178 INVESTIGATIONS
17

8

TOXICOLOGY HANDBOOK

• Spot urinary arsenic (normal <30 microgram/L or 400 nmol/L)
— Helpful to confirm ingestion.
— Levels after acute ingestion may be >1000 microgram/L
(13 500 nmol/L).
• 24-hour urinary arsenic excretion (normal <50 microgram/24 hours
or 675 nmol/24 hours)
— Better reflection of body burden.
— May be one or two orders of magnitude higher than normal
following acute exposure.
— 24-hour urine collection with speciation of non-toxic organic
and toxic inorganic forms is useful in assessing chronic
exposure.
• Blood levels
— Limited utility (may have a role in the assessment of acute
exposure in the anuric patient).
• Full blood count and coagulation profile
• Electrolytes
• Liver function tests
• Chest and abdominal X-rays (inorganic arsenic compounds are
radio-opaque)
MANAGEMENT
ERRNVPHGLFRVRUJ
• The immediate life-threat in early acute arsenic poisoning is
hypovolaemia and shock secondary to profound gastrointestinal
fluid losses.
• General supportive care measures and meticulous fluid
resuscitation are indicated, as outlined in Chapter 1.4:
Supportive care and monitoring.
Decontamination
• Activated charcoal does not bind arsenic and is not indicated.
• Cooperative patients who present following deliberate self-
poisoning with arsenic trioxide confirmed on abdominal X-ray
should undergo whole bowel irrigation with polyethylene glycol
(see Chapter 1.6: Gastrointestinal decontamination). Therapy
may be guided by monitoring arsenic transit on serial abdominal
SPECIFIC TOXINS
X-rays.
Antidotes
• Chelation is indicated where there are objective clinical features of
acute arsenic intoxication, or where subacute intoxication is
diagnosed on the basis of history of exposure, clinical features
and elevated urinary arsenic concentration (usually >200 179
microgram/L or 2700 nmol/L).
• Succimer is the agent of choice where oral administration is
available (see Chapter 4.28: Succimer).
TOXICOLOGY HANDBOOK
• Dimercaprol (British Anti-Lewisite (BAL)) should be administered
by IM injection where oral administration is not feasible because
of GI symptoms (see Chapter 4.7: Dimercaprol).
• 2,3-dimercaptopropane-1-sulfonic acid (DMPS) is not readily
available in Australasia but is suitable for IV or PO administration
and is preferred to dimercaprol for parenteral administration if
available.

• Chronic intoxication can be managed on an outpatient basis.
• Patients who are clinically well without gastrointestinal symptoms
at 12 hours following acute ingestion of arsenic are not poisoned
and may be discharged.
• Patients in whom clinical features develop following acute
ingestion of inorganic arsenic require admission for observation,
aggressive supportive care and chelation.
HANDY TIPS
• Chelation therapy of acute arsenic intoxication is not delayed
pending confirmatory levels.
• Discovery of elevated arsenic levels in an asymptomatic patient
undergoing a ‘heavy metal screen’ usually reflects increased
excretion of non-toxic organic arsenic compounds contained in
seafood.
• Patients should be instructed to avoid eating seafood or seaweed
for 3–4 days prior to 24-hour urinary arsenic level.
• Cutting or burning pine impregnated with copper chrome arsenate
preservative may cause symptoms of mucosal irritation from
ERRNVPHGLFRVRUJ
smoke or sawdust but does not cause arsenic poisoning.
Elevated arsenic levels are associated with long-term
occupational or domestic exposure to this compound.
PITFALL
• Ordering ‘heavy metal screens’ on patients with non-specific
symptoms without exposure assessment – these are rarely
clinically useful.
CONTROVERSIES
• There is no evidence to support any treatment intervention for
chronic arsenic poisoning, although vitamin and mineral
supplements and antioxidant therapy have been recommended.
SPECIFIC TOXINS
Prevention of exposure is the priority.

• Analysis of hair for metals is frequently subject to artefacts and is
not recommended.
• Relative efficacy of various chelating agents.
Presentations
Inorganic
Found naturally in ground water in some regions. Used in the production of
semiconductors, glass, pesticides and wood preservatives. Used medically to
180 induce remission in acute promyleocytic leukaemia. Found in many traditional and
herbal remedies.
18
Organic
0
Found predominantly in fish and shellfish as non-toxic arsenobetaine and arsenocholine.

TOXICOLOGY HANDBOOK
References
Graeme KA, Pollack CK. Heavy metal toxicity: arsenic and mercury. Journal of
Ratnaike RN. Acute and chronic arsenic toxicity. Postgraduate Medical Journal 2003;
79:391–396.
Xu Y, Wang Y, Zheng Q. Clinical manifestations and arsenic methylation after a rare
subacute arsenic poisoning accident. Toxicological Sciences 2008; 103(2):
278–284.
3.15 BACLOFEN
Large overdoses are characterised by rapid onset of delirium, respiratory
depression, coma and seizures and are potentially lethal without timely
institution of good supportive care.
RISK ASSESSMENT
• Ingestions >200 mg in adults are expected to cause significant
CNS effects including delirium, respiratory depression, coma and
seizures.
• Ingestions of smaller doses cause relatively mild symptoms.
• Good supportive care should result in a favourable outcome in all
cases.
Toxic mechanism
Baclofen is a synthetic derivative of GABA. At therapeutic doses, it acts principally on
spinal GABAB receptors inhibiting the release of excitatory amino acids (glutamate and
ERRNVPHGLFRVRUJ
aspartate). In overdose, brain GABA receptors are stimulated thereby inhibiting excitatory
neurotransmitters in the CNS and leading to sedation or coma. Baclofen also mediates
pre-and postsynaptic inhibition, causing seizures in overdose, and withdrawal
syndromes.
Toxicokinetics
Baclofen is rapidly and completely absorbed following oral administration. Peak serum
concentrations are achieved within 2 hours. It readily penetrates the blood–brain
barrier. Its volume of distribution is 0.7 L/kg and it is primarily excreted unchanged
in the urine. About 15% is metabolised by the liver. The mean elimination half-life is
3.5 hours.
CLINICAL FEATURES
• Clinical features of intoxication develop within 2 hours of
overdose and include:
SPECIFIC TOXINS
— Central nervous system
– Delirium
– Respiratory depression
– Profound and prolonged coma
– Seizures
— Cardiovascular
– Sinus bradycardia or tachycardia
– Hypertension or hypotension
– 1st degree heart block and QT prolongation (rare). 181
• Delirium is most evident just prior to the onset of coma or upon
awakening.
• Following large ingestions, coma may be profound. The patient
TOXICOLOGY HANDBOOK
may appear brain dead with fixed dilated pupils, hypotonia and
areflexia (including absent brainstem reflexes).
• The duration of coma is usually between 24 and 48 hours.
INVESTIGATIONS
MANAGEMENT
• Baclofen poisoning is a potentially life-threatening emergency
and resuscitation.
• Respiratory depression and coma necessitate advanced airway
management with early intubation and ventilation.
• Level of consciousness should be closely monitored during the
first few hours.
• Seizures, should they occur, are managed with titrated doses of
IV diazepam.
• Hypotension usually responds to fluid boluses. Inotropes are not
usually required.
• Tachycardia, bradycardia and hypertension are rarely severe
enough to require specific treatment.
Decontamination
• Activated charcoal is not indicated unless the airway is first
protected by endotracheal intubation.
ERRNVPHGLFRVRUJ
Antidotes
• None available.
• Following baclofen overdose, all patients are closely observed
for at least 4 hours.
• Patients who are asymptomatic at 4 hours following
ingestion may be discharged. Discharge should never occur
at night.
• Those manifesting minor CNS features such as delirium require
medical admission for ongoing supportive care until all clinical
SPECIFIC TOXINS
features resolve.
are admitted to an intensive care unit.
HANDY TIPS
• Baclofen overdose should be considered in any patient with
access to this agent who presents with coma. It is not detected
on routine drug screening.
182 • Baclofen is sometimes administered by continuous intrathecal
18
infusion via a reservoir and pump system. Pump malfunctions

2
resulting in even small intrathecal boluses can produce profound

TOXICOLOGY HANDBOOK
coma.
• Baclofen withdrawal syndrome occurs between 24 and
48 hours post cessation of baclofen and is manifested
by seizures, hallucinations, dyskinesia and visual
disturbances.
PITFALL
• Failure to reinstitute therapeutic baclofen following recovery from
an overdose, thereby precipitating a withdrawal syndrome which
may be mistaken for ongoing intoxication.
CONTROVERSY
• Management of intrathecal overdose is controversial. Current
recommendations, in addition to standard resuscitation measures,
include:
— Emptying reservoir
— Lumbar puncture and removal of 30–50 mL of CSF.
Presentations
Baclofen 10 mg tablets (100)
Baclofen 25 mg tablets (100)
Baclofen 0.05 mg/mL solution for intrathecal injection (1 mL, 20 mL)
Baclofen 2 mg/mL solution for intrathecal injection (5 mL)
Reference
Leung NY, Whyte IM, Isbister GK. Baclofen overdose: defining the spectrum of toxicity.
Emergency Medicine Australasia 2006; 18:77–82.
ERRNVPHGLFRVRUJ
3.16 BARBITURATES
Pentobarbitone, Phenobarbitone, Primidone, Thiopentone
Barbiturate overdose is an uncommon presentation, but can cause
profound and prolonged coma mimicking brain death. It is potentially
lethal but recognition of the diagnosis and good supportive care will
assure a favourable outcome.
RISK ASSESSMENT
• Ingestion of >8 mg/kg of phenobarbitone is expected to produce
toxic neurological symptoms in the non-tolerant individual.
Multiples of this dose are expected to produce profound
SPECIFIC TOXINS
prolonged coma.
• Self-administration of thiopentone or pentobarbitone (often by
medical or veterinary professionals) by the intravenous route is
likely to be lethal unless the mechanics of administration are such
that the rapid onset of coma prevents administration of all of the
intended dose.
• Children: most barbiturate toxicity in children occurs in the context
of therapeutic administration. Acute ingestion of >8 mg/kg of
phenobarbitone or >40 mg/kg of primidone would be expected to 183
produce neurological symptoms and requires medical assessment.
TOXICOLOGY HANDBOOK
Toxic mechanism
Barbiturates cause CNS depression by enhancing gamma-aminobutyric acid (GABA)
mediated inhibitory neurotransmission. They bind to the GABAA receptor complex and
increase the duration of chloride channel opening (in contradistinction to
benzodiazepines, which increase the frequency of opening). They also antagonise the
effect of the excitatory neurotransmitter glutamate by causing receptor blockade in the
CNS. Inhibition of medullary cardiorespiratory centres and hypothalamic autonomic
nuclei results in hypotension, hypothermia and respiratory arrest.
Toxicokinetics
All barbiturates are well absorbed from the gastrointestinal tract but only some agents
are clinically effective after oral administration. Because of their rapid redistribution from
the CNS and large volumes of distribution, the highly lipid soluble ‘short-acting’
barbiturates (thiopentone and pentobarbitone) are only useful medically if given by
intravenous administration. In contrast, the less lipid-soluble ‘long-acting’ barbiturates
such as phenobarbitone and primidone are distributed more slowly to the CNS, have
slower redistribution from the CNS, slower onset of clinical effect and smaller volumes of
distribution, of around 0.9 L/kg. For these reasons, they are suitable for oral
administration. All barbiturates are metabolised by saturable hepatic microsomal
pathways. Primidone is first metabolised to two active metabolites, phenobarbitone and
phenylethylmalonamide (PEMA). Phenobarbitone undergoes both enterohepatic and
enteroenteric recirculation. Approximately 25–50% of an ingested dose of
phenobarbitone is excreted unchanged in the urine. The elimination half-life of
phenobarbitone is long with considerable inter-individual variation (35–140 hours) and, as
a result of saturable kinetics, may be prolonged even further after overdose.
CLINICAL FEATURES
• Barbiturate toxicity may develop with therapeutic administration of
phenobarbitone or primidone. Symptoms are mild and neurological
in nature; they resolve with cessation of administration.
ERRNVPHGLFRVRUJ
• Barbiturate overdose is characterised by profound, prolonged and
potentially fatal depression of the central nervous and
cardiovascular systems.
• Onset of toxicity is within seconds to minutes of intravenous
overdose of thiopentone or pentobarbitone or within 1–2 hours of
ingestion of phenobarbitone or primidone.
– Ataxia, lethargy, slurred speech, drowsiness, vertigo and
nystagmus are followed by coma, hypotonia, hypothermia
and respiratory arrest at higher doses.
– Profound coma with complete loss of neurological
function can develop. Clinical features mimic brain death
with absent pupillary responses, vestibulo-ocular reflexes
and deep tendon reflexes.
SPECIFIC TOXINS
– Profound respiratory depression occurs, with Cheyne-

Stokes respiration progressing to apnoea.
— Cardiovascular system
– Tachycardia is frequently observed.
– In very large ingestions, hypotension occurs as a result
of depression of medullary vasomotor nuclei as well
as peripheral vasodilation and direct myocardial
depression.
184 — Other
– Hypothermia
18
4
– Reduced bowel sounds

– Skin bullae over pressure areas can occur (‘barbiturate
TOXICOLOGY HANDBOOK
blisters’) but are not specific for barbiturate toxicity.

• The duration of coma from poisoning with the short-acting
barbiturates (e.g. pentobarbitone) is not usually longer than 24–48
hours. In contrast, poisoning from long-acting barbiturates (e.g.
phenobarbitone, primidone) may last days or weeks necessitating
prolonged intensive care.
INVESTIGATIONS
• Serum barbiturate levels
— Phenobarbitone assays are readily available in most locations.
Other barbiturate assays can be obtained at specialised
centres.
— CNS depression correlates well with serum phenobarbitone
(see Table 3.16.1).
— Levels are useful to confirm ingestion and serial levels are
essential in the management of the comatose patient with
barbiturate poisoning. They allow monitoring of clinical
progress and are used to guide the use of enhanced
elimination techniques.
— A phenobarbitone level of >100 mg/L (>430 micromol/L)
prompts consideration of haemodialysis.
— Serum levels are not usually helpful in the absence
of coma.
ERRNVPHGLFRVRUJ
TABLE 3.16.1 Correlation of serum phenobarbitone levels and
clinical features
Level Clinical features
15–25 mg/L (65–108 micromol/L) Usual therapeutic range
30–80 mg/L (130–345 micromol/L) Increasing sedation
>80 mg/L (>345 micromol/L) Coma requiring intubation
• Other investigations may be required to exclude alternative
SPECIFIC TOXINS
causes of coma
— Note: the electroencephalogram (EEG) in barbiturate coma
may demonstrate profound suppression of activity to the point
of mimicking brain death.
MANAGEMENT
• All patients are managed in an area equipped for cardiopulmonary
monitoring and resuscitation. 185
TOXICOLOGY HANDBOOK
• The need for intubation is anticipated and performed early in the
patient with a declining level of consciousness.
Decontamination
• Activated charcoal 50 g is administered via a nasogastric tube to
the unconscious patient only after the airway is secured by
endotracheal intubation.
• Barbiturate pharmacokinetics render them amenable to enhanced
elimination techniques. The aim of instituting these interventions is
to reduce duration of coma and length of ventilation in intensive
care.
• Techniques of enhanced elimination are only considered for
poisoning by long-acting barbiturates (phenobarbitone, primidone)
where very slow endogenous clearance rates can otherwise result
in prolonged intensive care requirements.
• Multiple-dose activated charcoal (MDAC) substantially increases
the rate of elimination of phenobarbitone by interrupting
enterohepatic and enteroenteric circulation (see Chapter 1.7:
Enhanced elimination for details on performing this intervention).
It is indicated in the intubated comatose patient as long as bowel
sounds remain present.
• Haemodialysis, haemoperfusion and haemodiafiltration efficiently
remove phenobarbitone. These invasive interventions are
indicated for the patient with markedly elevated levels (>100 mg/L,
ERRNVPHGLFRVRUJ
>430 micromol/L) or where there are clinical manifestations of
severe poisoning, in particular persistent hypotension despite
inotropes and with evidence of end-organ dysfunction such as
oliguria. These interventions may also be considered where levels
are rising or have plateaued despite MDAC, or where continued
MDAC is not feasible due to ileus.
Antidotes
• None available.
• All children suspected of ingesting >8 mg/kg of phenobarbitone or
>40 mg/kg of primidone must be referred to hospital for
assessment and observation. They may be discharged home if
SPECIFIC TOXINS
they remain asymptomatic 6 hours post-ingestion.

• Adult patients who deliberately self-poison with phenobarbitone
or primidone should be observed in a closely monitored setting
for at least 6 hours. If they do not develop neurological signs or
symptoms during that time, further observation is not required.
• Patients who develop clinical evidence of toxicity require
admission for ongoing observation and serial barbiturate levels.
Significant CNS depression prompts endotracheal intubation and
186 intensive care admission.
18
HANDY TIPS
6
• Consider barbiturate poisoning in the patient with profound coma

TOXICOLOGY HANDBOOK
of unknown origin and hypotonia. Have a high index of suspicion

if the patient has a medical or veterinary background, or has a
history of epilepsy.
• A lower threshold for instituting haemoperfusion or haemodialysis
is appropriate in elderly patients and patients with coexisting
cardiac, respiratory or renal disease.
• Hypotensive patients are often intolerant of intermittent high-flow
dialysis so continuous modalities may be preferred, although at
the expense of compromised clearance.
PITFALLS
• Failure to consider the diagnosis of barbiturate toxicity. Along with
carbamazepine and valproate poisoning, it is an unusual but
eminently treatable cause of coma.
• Excessive focus on methods of enhancing elimination at the
expense of ensuring optimal supportive care measures are in place.
CONTROVERSIES
• Urinary alkalinisation has been shown to enhance elimination of
phenobarbitone but it is inferior to MDAC and not recommended.
• Although MDAC effectively enhances phenobarbitone elimination,
it has not been shown to reduce duration of coma or length of
stay in intensive care.
• There are no adequate clinical trials in support of haemodialysis
or other enhanced elimination techniques for the treatment of
barbiturate overdose. Recommendations are empiric and based
on risk–benefit analysis.
ERRNVPHGLFRVRUJ
Presentations
Pentobarbitone sodium: available as a veterinary preparation (used to euthanase animals)
Phenobarbitone 15 mg/5 mL elixir (100 mL, 500 mL)
Phenobarbitone 30 mg tablets (200)
Phenobarbitone sodium 200 mg/1 mL ampoules
Primidone 250 mg tablets (100, 200)
Thiopentone sodium 500 mg ampoules for reconstitution
References
Ebid A-HIM, Abdel-Rahman HM. Pharmacokinetics of phenobarbital during certain
enhanced elimination modalities to evaluate their clinical efficacy in management of
drug overdose. Therapeutic Drug Monitoring 2001; 23(3):209–216.
Frenia ML, Schauben JL, Wears RL et al. Multiple-dose activated charcoal compared to
urinary alkalinization for the enhancement of phenobarbital elimination. Clinical
SPECIFIC TOXINS
Toxicology 1996; 34(2):169–175.
Pond SM, Olson KR, Osteroloh JD et al. Randomized study of the treatment of
phenobarbital overdose with repeated doses of activated charcoal. Journal of the
American Medical Association 1984; 251(23):3104–3108.
Roberts DM, Buckley NA. Enhanced elimination in acute barbiturate poisoning – a
systematic review. Clinical Toxicology 2011; 49:2–12.
3.17 BENZODIAZEPINES
187
Alprazolam, Bromazepam, Clobazam, Clonazepam, Diazepam,
Flunitrazepam, Midazolam, Nitrazepam, Oxazepam, Temazepam,
Triazolam
TOXICOLOGY HANDBOOK
Also covers the non-benzodiazepine sedative-hypnotics: Zolpidem,
Zopiclone
Benzodiazepines are involved in up to one-third of deliberate self-
poisonings. An excellent prognosis is expected with supportive care of
CNS depression. Flumazenil is a useful diagnostic and therapeutic tool in
carefully selected cases.
RISK ASSESSMENT
• Isolated benzodiazepine overdose usually causes only mild
sedation, irrespective of the dose ingested, and can be easily
managed with simple supportive care.
• Alprazolam overdose is associated with a greater degree of CNS
depression and is more likely to require intubation and ventilation.
• Zolpidem and zopiclone rarely cause severe CNS or respiratory
depression when taken alone.
• Co-ingestion of other CNS depressants (e.g. alcohol, opioids,
antidepressants) increases the risk of complications, prolonged
length of stay and death.
• The elderly and patients with cardiorespiratory co-morbidities may
suffer greater complications.
• Children: ingestion of one or two benzodiazepine tablets usually
manifests as mild sedation and ataxia within 2 hours.
Toxic mechanism
Benzodiazepines act by enhancing gamma-aminobutyric acid (GABA) mediated
neurotransmission. They bind to the GABAA receptor complex and increase the
ERRNVPHGLFRVRUJ
frequency of chloride channel opening. Zolpidem and zopiclone are non-benzodiazepine
sedative-hypnotics that also act at the GABAA receptor complex.
Toxicokinetics
Benzodiazepines are rapidly absorbed orally. Most are highly protein bound and have
volumes of distribution that vary from 0.5 to 4 L/kg. Benzodiazepines undergo hepatic
metabolism. Many have active metabolites. For example, diazepam is metabolised to
N-desmethyldiazepam, oxazepam and temazepam, and alprazolam is metabolised to
1-and 4-hydroxyalprazolam. Duration of effect following overdose depends on CNS
tolerance and redistribution, rather than rate of elimination. Clinical features of
intoxication are poorly correlated to serum benzodiazepine levels.
CLINICAL FEATURES
• Onset of symptoms occurs within 1–2 hours. Ataxia, lethargy,
SPECIFIC TOXINS
slurred speech and drowsiness are followed by decreased

responsiveness. Profound coma is rare, except with alprazolam or
in mixed ingestions. Apnoea is a complication of airway
obstruction.
• In very large ingestions hypothermia, bradycardia and hypotension
may occur. Resolution of CNS depression usually occurs within
12 hours. More prolonged coma is common in the elderly.
INVESTIGATIONS
188 Screening tests in deliberate self-poisoning
18

8
TOXICOLOGY HANDBOOK
MANAGEMENT
These priorities can usually be managed along conventional lines,
as outlined in Chapter 1.2: Resuscitation.
• Monitor for urinary retention and place an indwelling catheter as
required.
Decontamination
• Activated charcoal is not indicated because the onset of sedation
occurs in the first few hours and simple supportive care ensures a
good outcome.
Antidotes
• Flumazenil is a competitive benzodiazepine antagonist with a
limited role in benzodiazepine overdose. Its indications include:
— Management of airway and breathing when resources are not
available to safely intubate and ventilate the patient
— Diagnostic tool to avoid further investigation
— Reversal of conscious sedation.
• For further information on the indications, contraindications and
administration see Chapter 4.9: Flumazenil.
ERRNVPHGLFRVRUJ
• Paediatric patients following accidental exposure may be
observed at home. If significant ataxia or drowsiness occurs,
referral to hospital for supportive care, usually overnight, is
appropriate.
• Patients with mild sedation are managed supportively in a ward
environment. They may be discharged when clinically well.
Discharge should not occur at night.
• Patients with significant CNS depression requiring intubation or
flumazenil infusion are admitted to a high-dependency or
intensive care unit (rare).
SPECIFIC TOXINS
HANDY TIPS
• Profound coma, tachycardia or 12-lead ECG changes
suggest a co-ingested agent and the need to revise the
risk assessment.
• Flumazenil may be life saving in selected patients when
the airway and breathing cannot be controlled by other
means.
PITFALL
189
• Administration of flumazenil when contraindicated because of
the risk of seizures due to co-ingestions or benzodiazepine
dependence.
TOXICOLOGY HANDBOOK
Presentations
Alprazolam 0.25 mg tablets (50) Lorazepam 2.5 mg tablets (50)
Alprazolam 0.5 mg tablets (50) Midazolam 5 mg/1 mL ampoules
Alprazolam 1 mg tablets (50) Midazolam 5 mg/5 mL ampoules
Alprazolam 2 mg tablets (50) Midazolam 15 mg/3 mL ampoules
Bromazepam 3 mg tablets (30, 60) Midazolam 50 mg/10 mL ampoules
Bromazepam 6 mg tablets (30, 60) Nitrazepam 5 mg tablets (25, 30, 50)
Clobazam 10 mg tablets (50) Oxazepam 15 mg tablets (25, 50, 90)
Clonazepam 0.5 mg tablets (100) Oxazepam 30 mg tablets (25, 50)
Clonazepam 2 mg tablets (100) Temazepam 10 mg tablets (25, 50)
Clonazepam 2.5 mg/1 mL liquid Triazolam 0.125 mg tablets (50)
Clonazepam 1 mg/2 mL ampoules Zolpidem 5 mg tablets (7, 14)
Diazepam 2 mg tablets (30, 50, 90) Zolpidem 10 mg tablets (2, 7, 10, 14, 20)
Diazepam 5 mg tablets (30, 50) Zolpidem 6.25 mg controlled-release
Diazepam 1 mg/mL liquid (5, 10, 100 mL) tablets (2, 14, 20)
Diazepam for injection 10 mg/2 mL Zolpidem 12.5 mg controlled-release
ampoules tablets (2, 14, 20)
Flunitrazepam 1 mg tablets (30) Zopiclone 7.5 mg tablets (10, 30)
Lorazepam 1 mg tablets (50)
References
Buckley NA, Dawson AH, Whyte IM. Relative toxicity of benzodiazepines in overdose.
British Medical Journal 1995; 310:219–221.
Garnier R, Guerault E, Muzard D et al. Acute zolpidem poisoning—analysis of 344 cases.
Journal of Toxicology–Clinical Toxicology 1994; 32(4):391–394.
Isbister GK, O’Regan L, Sibbritt D et al. Alprazolam is relatively more toxic than other
benzodiazepines in overdose. British Journal of Clinical Pharmacology 2004; 58(1):
88–95.
ERRNVPHGLFRVRUJ
3.18 BENZTROPINE
Frequently prescribed to patients on antipsychotics to ameliorate
dyskinaesias, this is a potent anticholinergic agent in overdose.
Excessive doses of benztropine, like other anticholinergic agents, are
sometimes consumed for recreational purposes.
RISK ASSESSMENT
• Any overdose of this agent is likely to precipitate anticholinergic
symptoms and require medical care.
• Anticholinergic syndrome can also occur with excessive
therapeutic doses.
SPECIFIC TOXINS
Toxicokinetics
There is little information on the pharmacokinetics of benztropine and even less on its
toxicokinetics. It appears to be well absorbed following oral administration. The onset of
therapeutic action is between 1 and 2 hours following oral administration. Metabolism is
probably hepatic with metabolites excreted in the urine.
Toxic mechanism
A synthetic drug containing the active tropine component of atropine and the
diphenylmethyl portion of diphenhydramine (antihistamine). It acts as an anticholinergic,
190 antihistaminergic and dopamine reuptake inhibitor.
19
0
CLINICAL FEATURES
• The clinical features are those of the anticholinergic syndrome
TOXICOLOGY HANDBOOK
(see Chapter 2.9: Anticholinergic syndrome) and include:

delirium, mydriasis, blurred vision, sinus tachycardia, warm
flushed dry skin, urinary retention and ileus.
• The maximal effects are normally observed within 6 hours and
may persist for a period from 12 hours to 5 days.
INVESTIGATIONS
• Other tests including EUC, CT head and lumbar puncture are
indicated if necessary to exclude important alternative diagnoses
such as intracranial infection.
MANAGEMENT
• Management is supportive and consists principally of sedation
with benzodiazepines, intravenous fluids and insertion of an
indwelling urinary catheter.
• Control of delirium can be challenging. Physical restraints are
sometimes necessary.
• Once adequate sedation is attained, one-to-one nursing in a calm,
closely monitored environment is essential to ensure patient safety.
• For a more detailed description of the management of
anticholinergic syndrome see Chapter 2.9: Anticholinergic
syndrome.
ERRNVPHGLFRVRUJ
Decontamination
• Activated charcoal may be useful if administered within 2 hours of
ingestion.
• It is of little value, not to mention technically challenging, once
delirium is established.
Antidote
• Physostigmine is considered in cases where the delirium is not
easily controlled with benzodiazepines (see Chapter 4.22:
Physostigmine).
SPECIFIC TOXINS
• Once initial control of delirium is attained, admission to a
high-dependency area with one-to-one nursing in a calm,
reassuring environment is essential. Staff should be aware that
the delirium might persist for several days.
HANDY TIP
• Insert an indwelling urinary catheter as soon as possible. Urinary
retention is almost universal in anticholinergic delirium and, if not 191
relieved, will exacerbate the patient’s agitation.
PITFALL
TOXICOLOGY HANDBOOK
• Failure to distinguish anticholinergic delirium from psychosis or
antisocial personality disorder.
CONTROVERSY
• The role of physostigmine: early use of this drug in severe
benztropine-induced anticholinergic delirium is increasingly
favoured.
Presentations
Benztropine mesylate 2 mg tablets (60)
Benztropine mesylate 2 mg/2 mL ampoules
3.19 BETA-BLOCKERS
Atenolol, Bisoprolol, Carvedilol, Esmolol, Metoprolol, Oxprenolol,
Pindolol, Propranolol, Sotalol
Isolated beta-blocker overdose, other than with propranolol or sotalol,
usually results in little or no toxicity and does not require specific care.
In contrast, propranolol or sotalol overdose may be life threatening.
RISK ASSESSMENT
• Toxicity does not correlate well with ingested dose.
• The following factors increase risk of severe toxicity:
— Ingestion of propanolol/sotalol
— Underlying heart or lung disease
ERRNVPHGLFRVRUJ
— Co-ingestion/regular treatment with calcium channel blocker
or digoxin
— Advanced age.
• The threshold dose for severe toxicity from propranolol may be as
little as 1 g.
• Toxicity usually manifests within the first few hours, with the
exception of overdose with controlled-release preparations or
sotalol.
• PR interval prolongation even in the absence of bradycardia is an
early sign of toxicity.
• Children: there is risk of toxicity following ingestion of any dose
of propranolol or sotalol. Ingestion of one or two tablets of other
agents does not cause significant toxicity.
SPECIFIC TOXINS
Toxic mechanism
Competitive antagonists at beta-1 and beta-2 receptors. Excessive beta-adrenergic
blockade leads to decreased intracellular cAMP concentration and resultant blunting of
the metabolic, chronotropic and inotropic effects of catecholamines. Propranolol also has
Na+-blocking effects (class I effects) leading to QRS widening and ventricular dysrhythmias
and, being lipid soluble, enters the CNS where it exerts direct toxicity. Sotalol also blocks
cardiac K+ channels interfering with cardiac repolarisation and leading to QT prolongation.
Toxicokinetics
192 Rapidly absorbed from GIT with peak serum concentrations occurring from 1 to 3 hours
post-ingestion. Rapidly distributed with a variable volume of distribution depending on
19
2
the agent. Propranolol is distinguished from other agents by being extremely lipophilic.
Metabolism and elimination vary with the different agents. Propranolol undergoes
TOXICOLOGY HANDBOOK
extensive hepatic metabolism with an elimination half-life of 12 hours but this may be
prolonged following overdose.
CLINICAL FEATURES
Occur within 4 hours with the onset of beta-blockade manifested by a
fall in heart rate. More severe manifestations may also occur during
this period following propranolol overdose or where there are other
factors predisposing to severe effects.
Cardiovascular
• Hypotension and bradycardia.
• Bradydysrhythmias observed include sinus bradycardia, 1st to 3rd
degree heart block, junctional or ventricular bradycardia.
• QRS widening is observed following propranolol overdose and the
magnitude is a predictor of ventricular dysrhythmias.
• QT prolongation and torsades de pointes are observed following
sotalol overdose.
Central nervous system
• Delirium, coma and seizures (propranolol).
Other
• Bronchospasm, pulmonary oedema.
• Hyperkalaemia.
• Hypo/hyperglycaemia.
INVESTIGATIONS
ERRNVPHGLFRVRUJ
• EUC
MANAGEMENT
• Acute beta-blocker poisoning is a potentially life-threatening
emergency managed in an area equipped for cardiorespiratory
monitoring and resuscitation.
• Resuscitation is most likely to be required following propranolol
overdose. Prompt intubation and ventilation and administration of
sodium bicarbonate are necessary to control ventricular
dysrhythmias (propanolol overdose is managed as a tricyclic
antidepressant overdose).
SPECIFIC TOXINS
• Immediate life-threats and treatment options include:
— Bradycardia and hypotension
– Atropine 0.01–0.03 mg/kg IV (temporising measure)
– Isoprenaline: 4 microgram/minute IV infusion
– Adrenaline
– High-dose insulin (see Chapter 4.15: Insulin (high dose))
— Wide QRS
– Sodium bicarbonate 1–2 mEq/kg boluses over 1–2 min
— Torsades de pointes (QT prolongation from sotalol)
– Isoprenaline 193
– Magnesium
– Overdrive pacing.
• Close clinical observation and continuous ECG monitoring are
TOXICOLOGY HANDBOOK
mandatory for at least 4 hours.
• Invasive monitoring of haemodynamic parameters is very useful in
sick patients.
Decontamination
• Activated charcoal may be administered to patients who present
within 2 hours but caution should be exercised following
propranolol overdose because of the risk of imminent coma and
seizures.
Antidotes
• High-dose insulin therapy may be considered (see Chapter 4.14:
Insulin (high dose)).

• Patients who remain asymptomatic and have a normal ECG at 6
hours following the overdose may be medically cleared.
• Patients with clinical or ECG manifestations of toxicity require
admission to an intensive care or high-dependency unit.
HANDY TIP
• Approach management of a propranolol overdose more like a
tricyclic antidepressant or other Na-channel blocker overdose
rather than a beta-blocker overdose.
ERRNVPHGLFRVRUJ
CONTROVERSIES
• Glucagon was previously regarded as a specific antidote to
beta-blocker poisoning but it offers no advantages over standard
inotropes and chronotropes. It is no longer used to treat beta-
blocker poisoning.
• Precise indications for high-dose insulin therapy (see Chapter
4.15: Insulin (high dose)) are as yet undefined but it is
increasingly instituted early in the management of propranolol
toxicity with haemodynamic compromise.
• The role of intravenous lipid emulsion in propranolol poisoning is
as yet undefined. It may be considered in life-threatening toxicity
where response to other interventions is inadequate (see Chapter
4.16: Intravenous lipid emulsion).
SPECIFIC TOXINS
Presentations
Atenolol 50 mg tablets (30) Metoprolol succinate controlled-release
Bisoprolol fumarate 2.5 mg tablets (28) 190 mg tablets (30)
Bisoprolol fumarate 5 mg tablets (28) Oxprenolol hydrochloride 20 mg tablets
Bisoprolol fumarate 10 mg tablets (28) (100)
Carvedilol 3.125 mg tablets (30) Oxprenolol hydrochloride 40 mg tablets
Carvedilol 6.25 mg tablets (60) (100)
Carvedilol 12.5 mg tablets (60) Pindolol 5 mg tablets (100)
Carvedilol 25 mg tablets (60) Pindolol 15 mg tablets (50)
194
Esmolol hydrochloride 100 mg/10 mL Propranolol hydrochloride 10 mg tablets
19
ampoules (100)
4
Metoprolol tartrate 50 mg tablets (100) Propranolol hydrochloride 40 mg tablets

TOXICOLOGY HANDBOOK
Metoprolol tartrate 100 mg tablets (60) (100)

Metoprolol tartrate 5 mg/5 mL ampoules Propranolol hydrochloride 160 mg tablets
Metoprolol succinate controlled-release (50)
23.75 mg tablets (15) Sotalol hydrochloride 80 mg tablets (60)
Metoprolol succinate controlled-release Sotalol hydrochloride 160 mg tablets (60)
47.5 mg tablets (30) Sotalol hydrochloride 40 mg/4 mL
Metoprolol succinate controlled-release ampoules
95 mg tablets (30)
References
Love J, Howell JM, Litovitz TL et al. Acute beta-blocker overdose: factors associated
with the development of cardiovascular morbidity. Journal of Toxicology–Clinical
Toxicology 2000; 38:275–281.
Reith DM, Dawson AH, Epid D et al. Relative toxicity of beta-blockers in overdose.
Journal of Toxicology–Clinical Toxicology 1996; 34:273–278.
Taboulet P, Cariou A, Berdeaux A et al. Pathophysiology and management of self-
poisoning with beta-blockers. Journal of Toxicology–Clinical Toxicology 1993;
31:531–551.
3.20 BUPROPION
This antidepressant agent is now used to suppress nicotine craving and
is only available as an extended-release preparation. There is a high risk
of seizures following an overdose of any amount and potential for
life-threatening cardiotoxicity occurs with very high doses. Supportive
care and adequate benzodiazepine sedation usually ensure a good
outcome.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• There is high risk of seizures following overdose of any amount.
• The first seizure usually occurs 2–8 hours following ingestion but
may be delayed up to 24 hours.
• Risk of seizures is increased if there is a preexisting lowered
seizure threshold or co-ingestion of other centrally acting
sympathomimetic or serotonergic agents.
• Severe cardiotoxicity, haemodynamic instability and cardiac
deaths have occurred at doses >9 g.
• Children: any child suspected of ingesting >10 mg/kg requires
assessment and observation in hospital.
SPECIFIC TOXINS
TABLE 3.20.1 Dose-related risk assessment: Bupropion
Dose Effect
Any dose Seizures, tachycardia, hypertension, tremors, agitation,

hallucinations, GI symptoms
>4.5 g Seizure risk of 50% and first seizure usually within

8 hours of ingestion
195
>9 g Seizures universal. Risk of cardiovascular complications,
including haemodynamic instability, prolonged QRS
and QT intervals and ventricular dysrhythmias
TOXICOLOGY HANDBOOK
Fatal without good supportive care
Toxic mechanism
Bupropion is a monocyclic antidepressant that suppresses nicotine craving by an
unknown mechanism. It increases the levels of CNS excitatory neuroamines by inhibiting
noradrenaline and dopamine reuptake. Also causes minimal serotonin reuptake inhibition
and moderate anticholinergic effects.
Toxicokinetics
Well absorbed orally with peak plasma levels occurring within 2–3 hours. Relatively large
volume of distribution (19.8–47 L/kg). Metabolised to active metabolites, which are
renally excreted.
CLINICAL FEATURES
• Clinical features develop progressively over 8 hours and include
tachycardia, hypertension, tremors, GI disturbance, agitation,
hallucinations, altered mental state and seizures.
• First seizure, heralded by neurological symptoms, usually occurs
during this period but may be delayed up to 24 hours
post-ingestion.
• Cardiovascular effects and ECG manifestations, including shock,
QRS widening and tachydysrhythmias, are reported after massive
overdose and usually manifest within 6 hours.
INVESTIGATIONS
ERRNVPHGLFRVRUJ
• Serial ECGs:
— Perform a 12-lead ECG on all patients at presentation and at
6 and 12 hours post-ingestion.
— For ingestions >4.5 g, 12-lead ECGs should be reviewed
every 2 hours (or if symptoms occur).
MANAGEMENT
• Bupropion overdose is a life-threatening emergency and is
and resuscitation.
• Early intubation and ventilation is indicated when the history and
SPECIFIC TOXINS
clinical progression suggest ingestion of >9 g.

— Seizures: give IV diazepam 2.5–5 mg and repeat if necessary
as described in Chapter 2.6: Seizures.
— Broad-complex tachycardias: manage aggressively with
intubation, hyperventilation and administration of sodium
bicarbonate 1–2 mmol/kg repeated every 1–2 minutes to
achieve serum alkalinisation as described in Chapter 4.25:
Sodium bicarbonate.
196 • Control agitation and tachycardia with titrated doses of IV
diazepam: give 2.5–5 mg every 2–5 minutes until gentle sedation
19
6
achieved.
• Continue close monitoring for at least 12 hours following
TOXICOLOGY HANDBOOK
ingestions of >9 g.
Decontamination
• Activated charcoal or other attempts at decontamination are
generally contraindicated because of the high risk of seizures,
unless the airway is secured.
• If >9 g is ingested and there is any evidence of toxicity, give
activated charcoal 50 g via the nasogastric tube following
Antidotes
• None available.
• Because of the risk of seizures following bupropion overdose, all
patients are observed with IV access in place for a minimum of
24 hours and until symptom-free.
• Patients who are clinically well at 24 hours following ingestion do
not require further medical observation. Discharge should never
occur at night.
• Patients with cardiotoxicity or seizures are admitted for monitoring
and supportive care until all clinical features of toxicity, including
sinus tachycardia, resolve.
ERRNVPHGLFRVRUJ
• Admission to ICU is indicated following massive ingestions (>9 g)
and for patients manifesting signs of significant cardiotoxicity.
HANDY TIP
• It is useful to give early prophylactic doses of IV benzodiazepines
in order to prevent seizures. The dose is titrated to achieve a
calm patient and a fall in the heart rate towards 100 bpm.
PITFALLS
• Failure to anticipate and prepare for delayed onset of symptoms
and seizures.
• Failure to administer benzodiazepines early and in sufficient dose.
• Administration of activated charcoal or initiation of whole bowel
SPECIFIC TOXINS
irrigation shortly before onset of seizures or cardiovascular
toxicity.
CONTROVERSIES
• The role of whole bowel irrigation (WBI): patients who present
early after massive ingestion of bupropion would appear to be
candidates for WBI. However, the risk of seizures occurring
during the procedure is such that it is contraindicated.
• Intravenous lipid emulsion and extracorporeal membrane 197
oxygenation have been advocated in the management of severe
bupropion toxicity but their role is as yet undefined.
TOXICOLOGY HANDBOOK
Presentations
Bupropion hydrochloride 150 mg sustained-release tablets (10, 60, 100, 120)
References
Balit CR, Lynch CN, Isbister GK. Bupropion poisoning: a case series. Medical Journal of
Australia 2003; 178:61–63.
Morazin F, Lumbroso A, Harry P. Cardiogenic shock and status epilepticus after massive
bupropion overdose. Clinical Toxicology 2007; 45(7):794–797.
Shepherd G, Veliz LI, Keys DC. Intentional bupropion overdoses. Journal of Emergency
Medicine 2004; 27(2):147–151.
Spiller HA, Bosic GM, Beuhler M et al. Unintentional ingestion of bupropion in children.
Journal of Emergency Medicine 2010; 38(3):332–336.
Starr P, Klein-Schwartz W, Spiller H et al. Incidence and onset of delayed seizures after
overdose of extended-release bupropion. American Journal of Emergency Medicine
2009; 27:911–915.
3.21 BUTTON BATTERIES

Ingestion of button batteries is almost exclusively a paediatric problem.
The majority pass through the gastrointestinal (GI) tract easily and
without complication. Larger batteries may lodge in the oesophagus,
causing significant complications including death, particularly if
diagnosis is delayed.
RISK ASSESSMENT
• Ingested batteries of diameter <20 mm are less likely to lodge in
the oesophagus and cause complications.
ERRNVPHGLFRVRUJ
• Ingested batteries of 20 mm diameter or greater are more likely to
lodge in the oesophagus and may cause severe local corrosive
injury within 2 hours.
• Local corrosive injury may also occur after insertion of smaller
batteries into the aural or nasal cavities.
• Age is an important predictor of severity with most severe
oesophageal injuries and fatalities occurring in children younger
than 4 years old.
• Delayed diagnosis of oesophageal button battery is associated
with worse outcome.
• A new battery is more dangerous than a spent battery when
lodged in the oesophagus; however, a spent battery retains
sufficient residual voltage to generate external current and can
still produce a corrosive injury.
SPECIFIC TOXINS
• Button batteries may contain manganese, silver, lithium or zinc

but the quantities available for absorption are insufficient to cause
systemic heavy metal toxicity.
Mechanism of injury
The most significant mechanism is the generation of hydroxide ions at the negative pole
of the battery caused by the current created through the adjacent tissue. The resulting
hydroxide accumulation produces results equivalent to localised alkaline corrosive injury
with tissue liquefactions and necrosis. Corrosive injury may develop within 2 hours of
198 lodgement. The severity and type of injury depends on the size of the current produced,
19
the location and orientation of the battery and the length of time it remains in the
8
oesophagus. Potential complications include oesophageal perforation, tracheo-

oesophageal fistula, aorto-oesophageal fistula and stricture formation.
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
• Many children are asymptomatic initially and present to hospital
because ingestion was witnessed or suspected by parents or
carers, or only after signs and symptoms of oesophageal
obstruction or injury develop.
• Where ingestion is unwitnessed, presentation may be delayed and
symptoms relatively non-specific. Button battery ingestion should
be considered in the presence of any of the following presenting
complaints: airway obstruction, cough, fever, dysphagia, sore
throat, chest discomfort, decreased oral intake, or coughing or
choking with eating and drinking.
• Where oesophageal injury is established, perforations and fistulas
may not be clinically evident for up to 28 days and strictures may
present after weeks to months.
INVESTIGATIONS
• History or suspicion of possible button battery ingestion
mandates plain anteroposterior (together with a lateral if an object
is identified above the diaphragm) X-ray of the neck, chest and
abdomen to localise the object and guide further management.
• Mercury and other heavy metal levels are not required routinely.
MANAGEMENT
Resuscitation and supportive care
• Resuscitation is rarely needed following acute ingestion unless
airway obstruction occurs.
ERRNVPHGLFRVRUJ
• Delayed presentation may require resuscitation following standard
protocols for cardiovascular collapse secondary to haemorrhage
or sepsis from oesophageal perforation, or for respiratory distress
from tracheo-oesophageal fistula.
Decontamination
• A button battery lodged in the oesophagus requires endoscopic
removal as soon as possible, and ideally within 2 hours of
ingestion.
• Endoscopy allows both removal of the battery and examination
for local complications to guide further management. The
presence of a mucosal burn prompts further investigation to
exclude perforation.
• A button battery located beyond the oesophagus in an
SPECIFIC TOXINS
asymptomatic child can be allowed to pass naturally.
• Batteries lodged in the nose or ears should be removed urgently.
• Children with a battery lodged in the oesophagus are referred for
urgent upper GI endoscopy and removal.
• Children in whom the battery has passed beyond the pylorus are
unlikely to develop complications and can be discharged with
advice to observe and return if symptoms develop. A follow-up 199
X-ray in 10–14 days to confirm passage may be reassuring if
passage in the stool has not been observed.
TOXICOLOGY HANDBOOK
HANDY TIPS
• Batteries typically have a ‘double ring’ or ‘halo’ shape on
anteroposterior view, and a ‘step-off’ appearance on lateral view
radiography.
• A high index of suspicion is required for investigation of small
children when a history of ingestion is not available.
• Magnet co-ingestion prompts urgent endoscopy and removal.
PITFALLS
• Failure to perform an X-ray in non-specific presentations where
button battery ingestion was not witnessed.
• Mistaking a button battery on X-ray for a coin, ECG electrode or
other external object. Batteries have a distinctive appearance and
lateral X-ray may help to identify the object.
• Delayed referral for endoscopic removal.
CONTROVERSIES
• Management of established oesophageal burns. Currently there
are no clearly established guidelines for management of
established burns with regard to repeat endoscopy, use of
steroids, antibiotic therapy and feeding.
• Management of button batteries located in the stomach. Some
authors recommend repeat X-ray at 4 days when a larger button
battery (>15 mm) is initially seen in the stomach, with endoscopic
retrieval if it has not passed through the pylorus by this time.
Smaller batteries can usually be managed expectantly at home
without repeat imaging.
ERRNVPHGLFRVRUJ
Sources
Button batteries are found in numerous devices including watches, cameras, remote
controls, electronic games and hearing aids. More recently, manufactured devices tend
to have smaller button batteries.
References
Jatana KR, Litovitz T, Reilly JS et al. Pediatric button battery injuries: 2013 task force
update. International Journal of Pediatric Otorhinolaryngology 2013; 77:1392–1399.
Litovitz T, Whitaker N, Clark L et al. Emerging battery-ingestion hazard: clinical
implications. Pediatrics 2010; 125:1168–1177.
3.22 CALCIUM CHANNEL BLOCKERS

SPECIFIC TOXINS
Amlodipine, Diltiazem, Felodipine, Lercanidipine, Nifedipine, Nimodipine,

Verapamil
Verapamil and diltiazem commonly cause cardiovascular collapse
following overdose and this may be delayed 4–16 hours after ingestion of
the extended-release (XR) preparations. The other agents are less
commonly associated with severe toxicity.
200 RISK ASSESSMENT

•
20
Ingestion of as little as 2–3 times the normal therapeutic dose of

0
verapamil or diltiazem XR preparations can cause severe toxicity

in susceptible individuals.
TOXICOLOGY HANDBOOK
• All deliberate self-poisonings are regarded as potentially

serious.
• Ingestion of >10 tablets of verapamil or diltiazem XR preparations
in an adult is likely to cause life-threatening toxicity.
• Onset of effects is up to 2 hours following ingestion of standard
preparations and 16 hours following XR preparations.
• The other calcium channel blockers (CCBs) are less likely to
cause life-threatening toxicity but may be associated with
bradycardia and hypotension.
• Co-ingestion of other cardiotoxic medications (e.g. beta-blockers
or digoxin) significantly increases the risk of serious toxicity.
• Advanced age and co-morbidities (e.g. cardiac disease) increase
the risk of significant toxicity.
• Children: ingestion of 2 or more tablets of any strength of
XR verapamil or diltiazem is potentially lethal. All children
suspected of ingesting any quantity of XR preparations should
be assessed in hospital. Children who are suspected of ingesting
>2 tablets of other preparations should also be assessed in
hospital.
Toxic mechanism
Calcium channel blockers prevent the opening of L-type calcium channels, resulting in
decreased calcium influx. This leads to vascular smooth muscle relaxation, slowing of
cardiac conduction and reduced force of cardiac contraction. Verapamil and diltiazem
cause central cardiac effects and peripheral vasodilation. The dihydropyridines chiefly
cause the latter. Hypotension results from severe peripheral vasodilation, bradycardia
and decreased contractility, associated with hyperglycaemia and lactic acidosis.
ERRNVPHGLFRVRUJ
Toxicokinetics
Calcium channel blockers are well absorbed, with peak levels occurring within 1–2 hours
(standard preparations) and 6–12 hours for XR preparations. However, in overdose peak
levels may not occur until 6 hours for standard preparations and 22 hours for XR
preparations. They have high volumes of distribution (e.g. verapamil 3–7 L /kg) and are
protein bound, but free levels often increase in overdose. Calcium channel blockers
undergo hepatic metabolism. There is a high first-pass effect after absorption, giving
bioavailability of approximately 40%. This may increase in overdose due to saturation of
hepatic metabolism. Verapamil is metabolised to an active metabolite norverapamil, and
diltiazem is metabolised to diacetyldiltiazem, which has vasodilator activity.
CLINICAL FEATURES
Following ingestion of standard preparations, onset of symptoms may
occur within 1–2 hours. In XR preparations, onset of significant toxicity
SPECIFIC TOXINS
may be delayed 12–16 hours with peak effects beyond 24 hours.
• Cardiovascular
— Bradycardia, first-degree heart block and hypotension (e.g.
SBP 95 mmHg) are early signs.
— Progression to refractory shock and death may occur.
— Myocardial ischaemia, stroke or non-occlusive mesenteric
ischaemia may complicate the clinical picture.
— Seizures and coma are rare.
— Coma usually indicates a co-ingested agent. 201
• Metabolic
— Hyperglycaemia and lactic acidosis occur in severe
intoxication.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
— Perform a 12-lead ECG at presentation and 8 hours post-
ingestion. Additional ECGs should be performed if there are
abnormal vital signs, and at 12, 18 and 24 hours following
ingestion of XR products.
— Profound bradycardia, first, second and third degree heart
block may occur.
• EUC
• BGL
• Serum calcium
• Serum lactate and arterial blood gases
• Chest X-ray
• Echocardiogram
• Pulmonary artery capillary wedge pressure, cardiac output,
systemic resistance
MANAGEMENT
Key objectives in the management of CCB poisoning are early
identification of patients at risk, initiation of appropriate monitoring,
consideration of gastrointestinal decontamination and referral to a
facility capable of advanced resuscitation and intensive care.
ERRNVPHGLFRVRUJ
• Acute CCB overdose is a time-critical emergency managed in an
area equipped for cardiorespiratory monitoring and resuscitation.
• Potential early life-threats that require immediate intervention
include:
— Hypotension
— Cardiac dysrhythmia
— Cardiac arrest.
• Mentation and airway protective reflexes are usually preserved
until cardiac arrest. Rapid-sequence endotracheal intubation and
ventilation may be required in cases of severe established toxicity.
• Early invasive blood pressure monitoring is advised for evolving
shock.
• Hypotension (SBP <90 mmHg) refractory to initial fluid
SPECIFIC TOXINS
resuscitation indicates the onset of significant toxicity and is an

indication to start high-dose insulin therapy (see Chapter 4.14:
Insulin (high-dose)). Calcium (see Chapter 4.2: Calcium),
although unlikely to be definitive treatment, can produce a
temporary increase in heart rate and blood pressure and may be
repeated up to three times while other therapies are started.
• Catecholamines are rarely effective in calcium-channel blocker
toxicity.
202 • Ventricular pacing should be used to bypass AV block and rates
should not exceed 60 beats/minute. Electrical capture is often
20
2
difficult to achieve, and may not be associated with improved

perfusion.
TOXICOLOGY HANDBOOK
• Cardiopulmonary bypass, ECMO and intra-aortic balloon pump

have been successfully used as extraordinary manoeuvres.
Decontamination
• Activated charcoal
— Administer to cooperative patients who present within 1 hour
of ingestion of standard preparations and 4 hours for XR
preparations.
— Administer to all intubated patients.
• Whole bowel irrigation (see Chapter 1.6: Gastrointestinal
decontamination)
— May be considered after a dose of activated charcoal in
cooperative adult patients without evidence of established
toxicity and who present within 4 hours of deliberate self-
poisoning with >10 tablets of verapamil XR or diltiazem XR.
• Rarely indicated (albumin dialysis has been advocated in selected
cases – see below).
Antidotes
• As discussed in Resuscitation, supportive care and monitoring
above:
— High-dose insulin euglycaemic therapy (see Chapter 4.15:
Insulin (high dose)). This is now regarded as the mainstay of
therapy in CCB poisoning and should be started as soon as
significant calcium channel blocker toxicity is detected
— Calcium (see Chapter 4.2: Calcium).
ERRNVPHGLFRVRUJ
• Patients who are clinically well with normal vital signs and 12-lead
ECG at 4 hours following standard preparations or 16 hours
following XR preparations may be discharged. Discharge should
not occur at night.
• Patients with manifestations of intoxication are referred to an
intensive care unit.
HANDY TIP
• If rapid-sequence endotracheal intubation is required, avoid
agents that will exacerbate hypotension or bradycardia. Preferred
agents include ketamine, fentanyl and rocuronium or vecuronium.
SPECIFIC TOXINS
PITFALLS
• Failure to anticipate potential for delayed onset of severe toxicity
following ingestion of XR preparations.
• Failure to initiate aggressive decontamination (activated charcoal
followed by whole bowel irrigation) in patients who present early
following life-threatening overdose of XR diltiazem or verapamil.
• Delay in institution of high-dose insulin therapy once evidence of
toxicity develops.
203
CONTROVERSIES
• The role of intravenous lipid emulsion in CCB poisoning is as yet
TOXICOLOGY HANDBOOK
undefined. It may be considered in life-threatening toxicity where
response to other interventions is inadequate (see Chapter 4.16:
Intravenous lipid emulsion).
• Albumin dialysis has been advocated in cardiogenic shock from
CCB poisoning, unresponsive to other measures.
Presentations
Benzothiazepines: Amlodipine besylate 10 mg/atorvastatin
Diltiazem 60 mg tablets (90) 40 mg tablets (30)
Diltiazem extended-release capsules Amlodipine besylate 10 mg/atorvastatin
180 mg (30) 80 mg tablets (30)
Diltiazem extended-release capsules Amlodipine besylate 5 mg tablets/
240 mg (30) olmesartan medoxomil 20 mg (10, 30)
Diltiazem extended-release capsules Amlodipine besylate 5 mg tablets/
360 mg (30) olmesartan medoxomil 40 mg (10, 30)
Dihydropyridines: Amlodipine besylate 10 mg tablets/
Amlodipine besylate 5 mg tablets (30) olmesartan medoxomil 40 mg (10, 30)
Amlodipine besylate 10 mg tablets (30) Amlodipine besylate 5 mg/olmesartan
Amlodipine besylate 5 mg/atorvastatin medoxomil 20 mg/hydrochlorothiazide
10 mg tablets (30) 12.5 mg tablets (10, 30)
Amlodipine besylate 5 mg/atorvastatin Amlodipine besylate 5 mg/olmesartan
20 mg tablets (30) medoxomil 40 mg/hydrochlorothiazide
Amlodipine besylate 5 mg/atorvastatin 12.5 mg tablets (10, 30)
40 mg tablets (30) Amlodipine besylate 5 mg/olmesartan
Amlodipine besylate 5 mg/atorvastatin medoxomil 40 mg/hydrochlorothiazide
80 mg tablets (30) 25 mg tablets (10, 30)
Amlodipine besylate 10 mg/atorvastatin Amlodipine besylate 10 mg/
10 mg tablets (30) olmesartan medoxomil 40 mg/
Amlodipine besylate 10 mg/atorvastatin hydrochlorothiazide 12.5 mg tablets
20 mg tablets (30) (10, 30)
ERRNVPHGLFRVRUJ
Amlodipine besylate 10 mg/ Felodipine 5 mg/ramipril 5 mg modified-
olmesartan medoxomil 40 mg/ release tablets (30)
hydrochlorothiazide 25 mg tablets Lercanidipine hydrochloride 10 mg tablets
(10, 30) (28, 30, 100, 500)
Amlodipine besylate 5 mg/perindopril Lercanidipine hydrochloride 20 mg tablets
arginine 5 mg tablets (10, 30) (28, 30, 100, 500)
Amlodipine besylate 5 mg/perindopril Lercanidipine hydrochloride 10 mg/
arginine 10 mg tablets (10, 30) enalapril maleate 10 mg tablets (28)
Amlodipine besylate 10 mg/perindopril Lercanidipine hydrochloride 10 mg/
arginine 5 mg tablets (10, 30) enalapril maleate 20 mg tablets (28)
Amlodipine besylate 10 mg/perindopril Nifedipine 10 mg tablets (60)
arginine 10 mg tablets (10, 30) Nifedipine 20 mg tablets (60)
Amlodipine besylate 5 mg/valsartan 80 mg Nifedipine controlled-release tablets
tablets (7, 14, 28, 30, 56) 20 mg (30)
Amlodipine besylate 5 mg/valsartan Nifedipine controlled-release tablets
SPECIFIC TOXINS
160 mg tablets (7, 14, 28, 30, 56) 30 mg (30)

Amlodipine besylate 5 mg/valsartan Nifedipine controlled-release tablets
320 mg tablets (7, 14, 28, 30, 56) 60 mg (30)
Amlodipine besylate 10 mg/valsartan Nimodipine 30 mg tablets (100)
160 mg tablets (7, 14, 28, 30, 56) Nimodipine 10 mg/50 mL ampoules
Amlodipine besylate 10 mg/valsartan Phenylalkylamines:
320 mg tablets (7, 14, 28, 30, 56) Verapamil hydrochloride immediate-
Amlodipine besylate 5 mg/valsartan release tablets 40 mg (100)
160 mg/hydrochlorothiazide 12.5 mg Verapamil hydrochloride immediate-
tablets (7, 28) release tablets 80 mg (100)
204 Amlodipine besylate 5 mg/valsartan Verapamil hydrochloride immediate-
160 mg/hydrochlorothiazide 25 mg release tablets 120 mg (100)
20
4
tablets (7, 28) Verapamil hydrochloride immediate-

Amlodipine besylate 10 mg/valsartan release tablets 160 mg (60)
TOXICOLOGY HANDBOOK
160 mg/hydrochlorothiazide 12.5 mg Verapamil hydrochloride sustained-release

tablets (7, 14, 28, 30, 56) capsules 160 mg (30)
Amlodipine besylate 10 mg/valsartan Verapamil hydrochloride sustained-release
160 mg/hydrochlorothiazide 25 mg capsules 240 mg (30)
tablets (7, 14, 28, 30, 56) Verapamil hydrochloride sustained-release
Amlodipine besylate 10 mg/valsartan tablets 180 mg (30)
320 mg/hydrochlorothiazide 25 mg Verapamil hydrochloride sustained-release
tablets (7, 14, 28, 30, 56) tablets 240 mg (30)
Felodipine extended-release tablets Verapamil hydrochloride 5 mg/2 mL
2.5 mg (30) ampoules
Felodipine extended-release tablets 5 mg Verapamil hydrochloride 180 mg/
(30) trandolapril 2 mg sustained-release
Felodipine extended-release tablets 10 mg tablets (28)
(30) Verapamil hydrochloride 240 mg/
Felodipine 2.5 mg/ramipril 2.5 mg trandolapril 4 mg sustained-release
modified-release tablets (30) tablets (28)
References
Buckley N, Dawson A, Whyte I. Calcium channel blockers. Medicine 2007; 35(11):134–139.
DeWitt CR, Waksman JC. Pharmacology, pathophysiology and management of calcium
channel blocker and β-blocker toxicity. Toxicological Reviews 2004; 23(4): 223–238.
Mégarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/
euglycaemia) therapy in acute calcium channel antagonist and β-blocker toxicity.
Toxicological Reviews 2004; 23(4): 215–222.
Olsen KR, Erdman AR, Woolf AD et al. Calcium channel blocker ingestion: an evidence-
based guideline for out-of-hospital management. Clinical Toxicology 2005;
43:797–822.
Pichon N, Dugard A, Clavel M et al. Extracorporeal albumin dialysis in three cases of
acute calcium channel blocker poisoning with life-threatening refractory cardiogenic
shock. Annals of Emergency Medicine 2012; 59:540–544.
ERRNVPHGLFRVRUJ
Yuan TH, Kerns WP, Tomaszewski CA et al. Insulin-glucose as an adjunctive therapy for
severe calcium channel antagonist poisoning. Clinical Toxicology 1999; 37(4):
463–474.
3.23 CANNABINOIDS (marijuana)

Delta-9-tetrahydrocannabinol, delta-8-tetrahydrocannabinol, cannabinol,
cannabidiol
Slang terms include hashish, dope, marijuana, ganja, grass, pot
and weed.
Marijuana is the most widely used recreational illicit drug in Australasia.
SPECIFIC TOXINS
It is a psychoactive drug that can cause unpleasant but benign
symptoms in adults. Cannabis ingestion by children leads to significant
CNS depression.
RISK ASSESSMENT
• There are no reports of death directly attributed to recreational
use of marijuana.
• Adults may experience unpleasant symptoms in a dose-
dependent manner: 205
— Low-dose effects: 50 microgram/kg (3–4 mg) are associated
with mild sedation, disinhibition, mild disorientation and
euphoria
TOXICOLOGY HANDBOOK
— High-dose effects: 250 microgram/kg (15 mg) are associated
with tachycardia, postural hypotension, CNS depression,
anxiety, perceptual disturbances and even psychotic
symptoms.
• Co-ingestion of other CNS depressants has an additive effect.
• Chronic use leads to long-term neuropsychiatric sequelae
and a withdrawal syndrome is described in habitually heavy
users.
• Children: ingestion may lead to life-threatening coma in a child.
Toxic mechanism
Marijuana is a psychoactive drug with central sympathomimetic and antiemetic
properties. It acts on cannabinoid receptors in the central and peripheral nervous system
(CB1) and on immune cells (CB2). It has been shown to augment dopamine release.
Delta-9-tetrahydrocannabinoid (THC) is the most potent component.
Toxicokinetics
Rapidly and completely absorbed by inhalation. Bioavailability is reduced if ingested.
Cannabinoids are highly protein bound, lipid soluble and have large volumes of
distribution (10 L/kg). They undergo hepatic metabolism to form active and inactive
metabolites that are excreted in the urine. Elimination half-life of the metabolites is
several days.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, psychiatric
sequelae or withdrawal. In adults, acute symptoms last up to 4 hours
following inhalation and up to 8 hours following ingestion. Clinical
features of intoxication include:
ERRNVPHGLFRVRUJ
— Ataxia, incoordination, impaired judgement
— Sedation
— CNS depression
— Coma in children that can last up to 36 hours
• Cardiovascular
— Tachycardia
— Orthostatic hypotension
— Syncope
• Psychiatric
— Euphoria and relaxation
— Agitation
— Anxiety and panic attacks
— Time distortion, hallucinations, delusions
SPECIFIC TOXINS
— Acute psychosis
• Respiratory complications (rare)
— Pneumothorax
— Pneumomediastinum.
Chronic cannabis users may also present repeatedly to emergency
departments with cannabinoid hyperemesis syndrome. This syndrome
is characterised by repeated episodes of vomiting separated by
weeks or months and can be difficult to control. Severe cases may be
206
complicated by acid–base disturbance and acute renal failure.
20
Repeated therapeutic showering or bathing in hot water to achieve

6
temporary control of symptoms is frequently observed. The diagnosis

TOXICOLOGY HANDBOOK
should only be made after alternative aetiologies are excluded. The

vomiting resolves with abstinence.
INVESTIGATIONS
• Serum or urine cannabinoid levels are not readily available and do
not assist acute management. They are sometimes performed for
forensic indications.
• Spot blood levels of 11-carboxy-THC greater than 40
microgram/L indicate chronic consumption.
• Urine screening tests may be positive for 1–3 days after acute
use, or 10 days to 4 weeks after chronic use.
• Passive smoking of cannabis may give positive results after an
acute exposure for several days on some screening tests.
• False positive urine screens occur.
MANAGEMENT
• Cannabis intoxication is benign and self-limiting.
• Tachycardia and hypotension are managed with fluids and
sedation as appropriate.
• Treat severe agitation with IV diazepam 5 mg every 2–5 minutes
until sedation is achieved. Once sedated, the patient should be
rousable to voice but calm.
ERRNVPHGLFRVRUJ
• Adult patients with mild dysphoria or agitation are given oral
diazepam 5 mg and reassured.
• Cannabinoid hyperemesis syndrome sufferers may require
intravenous fluids and antiemetics.
Decontamination
Antidotes
• None available.
SPECIFIC TOXINS
• Children who may have ingested marijuana should be observed in
hospital for 4 hours. If they do not develop symptoms during that
period they may then be safely discharged.
• Patients with intoxication adequately controlled with
benzodiazepine sedation may be managed supportively in a ward
environment. They may be discharged when asymptomatic.
Patients with cannabinoid hyperemesis syndrome frequently
require short admissions for intravenous fluids and antiemetic
therapy. They should be counselled and supported to achieve and 207
maintain abstinence following discharge.
TOXICOLOGY HANDBOOK
HANDY TIPS
• Cannabis poisoning is not life threatening and acute toxicity is
very low.
• Profound coma or 12-lead ECG changes suggest a co-ingested
agent and the need to revise the risk assessment.
PITFALL
• Failure to anticipate the potential in paediatric ingestions for rapid
onset of coma, hypotonia, abnormal movements, tachycardia and
bradycardia lasting 24–36 hours.
CONTROVERSY
• Cannabis impairs coordination, cognition and behaviour in a
dose-dependent manner; however, the impairment of driving
ability and correlation with blood or urine cannabinoid levels has
not been established.
Presentations
Any part or extract of the hemp plant (Cannabis sativa) can be dried or converted to a
resin extract.
References
Allen JH, de Moore GM, Heddle R et al. Cannabinoid hyperemesis: cyclical hyperemesis
in association with chronic cannabis abuse. Gut 2004; 53:1566–1570.
Hall W, Solowij N. Adverse effects of cannabis. Lancet 1998: 352:1611–1615.
Reece AS. Chronic toxicology of cannabis. Clinical Toxicology 2009; 47(6):517–524.
Sydney S, Beck JE, Tekawa IE et al. Marijuana use and mortality. American Journal of
Public Health 1997; 87:585–590.
ERRNVPHGLFRVRUJ
3.24 CARBAMAZEPINE
Deliberate self-poisoning with this anticonvulsant agent results in
predictable dose-dependent CNS and anticholinergic effects.
Management is primarily supportive with the selected use of enhanced
elimination techniques.
RISK ASSESSMENT
• Clinical features are dose dependent (see Table 3.24.1) but onset
varies depending on whether the preparation is immediate or
controlled release.
SPECIFIC TOXINS
TABLE 3.24.1 Dose-related risk assessment: Carbamazepine
Dose Effect
20–50 mg/kg Mild-to-moderate CNS and anticholinergic effects
>50 mg/kg Fluctuating mental status with intermittent

agitation and risk of progression to coma
within the first 12 hours
208 Risk of hypotension and cardiotoxicity with
20
extreme doses
8
TOXICOLOGY HANDBOOK
• Following larger overdoses, anticholinergic effects may be

prominent prior to development of coma.
• Following massive ingestions, coma is anticipated to last several
days, secondary to ongoing absorption, slow elimination and the
presence of an active metabolite.
• Pregnancy: carbamazepine is teratogenic. Overdose in the first
trimester warrants referral for further antenatal assessment.
• Children: one 400-mg tablet is enough to cause significant
intoxication in a toddler and suspected ingestion of this dose or
greater warrants observation in hospital for 8 hours.
Toxic mechanism
Carbamazepine is structurally similar to the tricyclic antidepressant imipramine. It
inhibits inactivated sodium channels, thus preventing further action potentials. It also
blocks noradrenaline reuptake and is an antagonist at muscarinic, nicotinic and
N-methyl-D-aspartate central adenosine receptors.
Toxicokinetics
Carbamazepine is slowly and erratically absorbed. Following large overdoses, ileus
secondary to anticholinergic effects may result in ongoing absorption for several days.
Carbamazepine has a small volume of distribution (0.8–1.2 L/kg) and undergoes hepatic
metabolism by cytochrome P450 3A4 to form an active metabolite (carbamazepine
10,11-epoxide). This is metabolised to inactive metabolites that are excreted in the urine.
CLINICAL FEATURES
Clinical features of intoxication are usually evident within 4 hours of
ingestion, but may not reach their most severe extent until 8–12
hours, particularly with controlled-release preparations. Ongoing
ERRNVPHGLFRVRUJ
erratic absorption for several days frequently complicates large
overdoses producing a fluctuating clinical course.
• Mild-to-moderate CNS effects include nystagmus, dysarthria,
ataxia, sedation, delirium, mydriasis, ophthalmoplegia and
myoclonus.
• Anticholinergic effects, such as urinary retention, tachycardia and
dry mouth, are common in the early stages.
• Coma requiring intubation and ventilation may be delayed until
8–12 hours post-ingestion. A fluctuating mental status with
intermittent agitation may also occur.
• Large overdoses may be complicated by seizures, hypotension
and cardiac conduction abnormalities. Cardiac dysrhythmias (VT,
VF, asystole) are associated with massive overdoses.
SPECIFIC TOXINS
INVESTIGATIONS
• Serum carbamazepine levels (see Table 3.24.2)
— Useful to confirm the diagnosis.
— In mild-to-moderate intoxication management is guided by
clinical features, so repeated levels are not required. 209
— In cases with coma, monitoring of carbamazepine levels every
6 hours is essential to monitor the patient’s clinical course.
TOXICOLOGY HANDBOOK
TABLE 3.24.2 Correlation of serum levels and clinical features:
Carbamazepine
Carbamazepine level Clinical features
8–12 mg/L (34–51 micromol/L) Therapeutic range
>12 mg/L (51 micromol/L) Nystagmus and ataxia
>20 mg/L (85 micromol/L) CNS and anticholinergic effects
>40 mg/L (170 micromol/L) Coma, seizures and cardiac

conduction abnormalities

— Ingestions >50 mg/kg may be associated with evidence of
sodium channel blockade (1st degree heart block and
increased QRS duration). A repeat ECG should be examined
at the onset of significant intoxication, and every 12 hours
thereafter. Abnormalities prompt more frequent ECG
evaluation.
MANAGEMENT
ERRNVPHGLFRVRUJ
• In the rare event of ventricular dysrhythmias, resuscitation should
include the use of IV bolus sodium bicarbonate, as outlined in
Chapter 4.25: Sodium bicarbonate.
majority of patients. General supportive care measures are
indicated, as outlined in Chapter 1.4: Supportive care and
monitoring.
• Seizures and agitated delirium may be managed with
benzodiazepines as outlined in Chapter 2.6: Seizures and
Chapter 2.7: Delirium and agitation.
Decontamination
• Activated charcoal is considered for ingestions <50 mg/kg or
larger ingestions of controlled-release preparations that present
SPECIFIC TOXINS
very early and are asymptomatic.

• If CNS toxicity is already evident, activated charcoal is only
administered after the patient is intubated.
• Methods of enhanced elimination are frequently considered in
severe carbamazepine intoxication but their effect on outcome
has not been studied in controlled trials (see Chapter 1.7:
Enhanced elimination).
210
• Multiple-dose activated charcoal is indicated in intubated
21
patients. It is ceased immediately if bowel sounds

0
disappear.
• Extracorporeal elimination techniques are useful in severe
TOXICOLOGY HANDBOOK
intoxication. Haemodialysis or haemodiafiltration removes

carbamazepine effectively. Indications include prolonged coma
with serum levels greater than 40 mg/L (170 micromol/L) after 48
hours or haemodynamic instability.
Antidotes
• None available.
• Children suspected of ingesting 20 mg/kg of carbamazepine
should be observed in hospital for at least 8 hours and
overnight.
• Patients who are clinically well without sedation or anticholinergic
effects at 8 hours following ingestion do not require further
monitoring or investigation.
• Patients with nystagmus, ataxia, drowsiness and anticholinergic
effects are managed supportively in a ward environment after an
initial 8-hour period of observation in the emergency department
or high-dependency unit.
• Patients with coma requiring intubation or seizures require
admission to the intensive care unit.
HANDY TIP
• In suspected paediatric ingestion, an undetectable serum
carbamazepine level any time after the first hour excludes
ingestion and allows immediate discharge.
ERRNVPHGLFRVRUJ
PITFALLS
• Failure to appreciate the potential for delayed onset of toxicity.
• Failure to detect urinary retention and place an indwelling urinary
catheter.
CONTROVERSY
• The indications for multiple-dose activated charcoal and
extracorporeal elimination. The decision remains one of clinical
judgement involving a risk–benefit analysis.
Presentations
Carbamazepine tablets 100 mg (200)
Carbamazepine tablets 200 mg (200)
SPECIFIC TOXINS
Carbamazepine controlled-release tablets 200 mg (200)
Carbamazepine controlled-release tablets 400 mg (200)
Carbamazepine suspension 20 mg/mL (300 mL)
References
Apfelbaum JD, Carabati EM, Kerns WP II. Cardiovascular effects of carbamazepine
toxicity. Annals of Emergency Medicine 1995; 25:631–635.
Hojer J, Malmlund HO, Berg A. Clinical features in 28 consecutive cases of laboratory
confirmed massive poisoning with carbamazepine alone. Journal of Toxicology
– Clinical Toxicology 1993; 31:449–458.
Spiller HA. Management of carbamazepine overdose. Pediatric Emergency Care 2001; 211
17(6):452–456.
Tapolyai M, Campbell M, Dailey K et al. Hemodialysis is as effective as hemoperfusion
for drug removal in carbamazepine poisoning. Nephron 2002; 90(2):213–215.
TOXICOLOGY HANDBOOK
3.25 CARBON MONOXIDE
Carbon monoxide is a common cause of poisoning death. Acute effects
are secondary to tissue hypoxia. Delayed neurological sequelae are
secondary to an incompletely understood cascade of endovascular
oxidative injury and inflammation.
RISK ASSESSMENT
• Carbon monoxide poisoning deaths almost always occur
pre-hospital. For those who arrive at hospital, risk assessment
attempts to identify those at risk of myocardial injury and
long-term neuropsychological sequelae.
• Acute deliberate self-poisoning by car exhaust fumes usually
involves exposure to high concentrations of CO for a limited
duration and lower risk of long-term sequelae.
• Accidental occupational or domestic exposure often involves
exposure to lower concentrations of CO for a prolonged duration
and higher risk of long-term sequelae.
• High-risk features include:
— Significant loss of consciousness or coma
— Persistent neurological dysfunction (e.g. confusion)
— Abnormal cerebellar examination
— Metabolic acidosis
— Myocardial ischaemia
— Age over 55 years.
ERRNVPHGLFRVRUJ
• Outcome is poorly correlated with carboxyhaemoglobin level.
• Pregnancy: fetal haemoglobin binds CO more avidly, rendering
the fetus more susceptible to injury.
Toxic mechanism
Carbon monoxide has 210 times the affinity for haemoglobin than oxygen. Binding
therefore renders haemoglobin oxygen transport less effective. Hypoxia results. In
addition, CO binds to intracellular cytochromes. Carbon monoxide also initiates
endothelial oxidative injury, lipid peroxidation and an inflammatory cascade. This process
is probably responsible for the delayed neurological sequelae.
Toxicokinetics
The elimination half-life of carboxyhaemoglobin (COHb) is determined by the dissolved
oxygen tension of the blood and varies as follows:
•
SPECIFIC TOXINS
Room air: 240 min

• 100% oxygen: 90 min
• 100% oxygen at three atmospheres: 23 min.
CLINICAL FEATURES
Following acute exposure, most patients present with headache,
nausea and varying degrees of altered mentation, which rapidly
resolve with oxygen therapy. A history of transient loss of
consciousness is common. Potential clinical manifestations include:
212 • Central nervous system
— Headache, nausea, dizziness
21
2
— Confusion, poor concentration, mini mental status examination

(MMSE) errors
TOXICOLOGY HANDBOOK
— Incoordination and ataxia

— Seizures and coma
• Cardiovascular
— Tachycardia and hypertension
— Ischaemic ECG changes
— Hypotension
— Dysrhythmias
— Acute myocardial infarction
• Respiratory
— Non-cardiogenic pulmonary oedema
• Metabolic
— Lactic acidosis
— Rhabdomyolysis
— Hyperglycaemia
• Other
— Disseminated intravascular coagulation
— Bullae, alopecia, sweat gland necrosis.
Persistent neurological sequelae are usually evident from the time
of poisoning and seen in up to 30% of survivors at 1 month.
Neuropsychiatric sequelae persist in 6–10% at 12 months. Symptoms
are non-specific and include personality changes, poor concentration,
dementia, psychosis, parkinsonism, ataxia, peripheral neuropathy and
hearing loss.
INVESTIGATIONS
ERRNVPHGLFRVRUJ
• Carboxyhaemoglobin level (COHb)
— Confirms the diagnosis and loosely correlates to symptoms
when measured shortly after the termination of exposure (see
Table 3.25.1). Most patients presenting to the emergency
department by ambulance have already received oxygen
therapy and the COHb measured on arrival does not correlate
well with symptoms
TABLE 3.25.1 Correlation of COHb levels and clinical features
Level Clinical features
SPECIFIC TOXINS
<10% Background level in a smoker
10% Usually asymptomatic, slight headache
20% Dizziness, nausea, dyspnoea, throbbing headache
30% Vertigo, ataxia, visual disturbance
40% Confusion, coma, seizures, syncope

213
50% Cardiovascular and respiratory failure,
dysrhythmias, seizures and death
TOXICOLOGY HANDBOOK
• Serum lactate
• Full blood count
• EUC
• Troponin
• β-HCG
• Mini mental status examination (MMSE)
• Cranial CT or MRI brain
— May demonstrate cerebral oedema, cerebral atrophy, basal
ganglia injury or cortical demyelination in severe cases
• Neuropsychiatric testing
— May be indicated at 1–2 months to investigate persistent or
delayed neurological symptoms.
MANAGEMENT
• Administration of high-flow supplemental oxygen as soon as
possible.
Decontamination
• Remove from exposure and apply supplemental oxygen.
ERRNVPHGLFRVRUJ
• Elimination of CO is enhanced by:
— Normobaric oxygen
– All patients should receive 100% oxygen or high-flow
oxygen via a non-rebreathing mask until all symptoms
have resolved and for at least 8 hours
– Pregnant patients receive 100% oxygen for 24 hours
while fetal wellbeing is assessed
— Hyperbaric oxygen (HBO)
– May be indicated in patients with one or more of the risk
factors listed above but indications and effectiveness are
controversial (see Controversies below)
– All pregnant patients should be considered for HBO.
SPECIFIC TOXINS
Antidotes
• None available.
• All symptomatic patients immediately receive supplemental
oxygen and are referred to hospital for evaluation.
• Continue oxygen in hospital until all symptoms resolve and for at
least 8 hours.
214 • Patients with persistent symptoms of end-organ ischaemia are
managed in a high-dependency or intensive care setting.
21
• Arrange follow-up at 1–2 months to assess general

4
neuropsychiatric function.
TOXICOLOGY HANDBOOK
HANDY TIP
• The patient who presents following accidental occupational or
domestic poisoning represents an index case. Investigation of the
source and other potential victims is indicated.
PITFALLS
• Failure to diagnose accidental occupational or domestic poisoning
in patients who present with headache or other non-specific
symptoms.
• Failure to perform a detailed neurological examination and
MMSE.
CONTROVERSIES
• The duration of normobaric oxygen treatment.
• The indications for and effectiveness of HBO. Randomised
controlled trials have failed to establish whether the
administration of HBO to patients with CO poisoning reduces the
incidence or severity of adverse neurological outcomes. While
HBO cannot be routinely recommended, there may be a small
group of patients with severe poisoning for whom there is some
(unproven) benefit. Clinical judgement and consideration of local
logistics is required.
Sources
Incomplete combustion of hydrocarbon fuels
Methylene chloride (dichloromethane) is a solvent metabolised to CO in vivo.
ERRNVPHGLFRVRUJ
References
Buckley NA, Isbister GK, Stokes B et al. Hyperbaric oxygen for carbon monoxide
poisoning: a systematic review and critical analysis of the evidence. Toxicological
Reviews 2005: 24(2):75–92.
Buckley NA, Juurlink DN, Isbister G et al. Hyperbaric oxygen for carbon monoxide
poisoning. Cochrane Database of Systematic Reviews 2011; 4:CD002041.
Hampson NB, Piantodosi CA, Thom SR, Weaver LK. Practice recommendations in the
diagnosis, management, and prevention of carbon monoxide poisoning. American
Journal of Respiratory and Critical Care Medicine 2012; 186:1095–1101.
Scheinkestel CD, Bailey M, Myles PS et al. Hyperbaric or normobaric oxygen for acute
carbon monoxide poisoning: a randomised controlled clinical trial. Medical Journal of
Australia 1999; 170:203–210.
Weaver LK, Hopkins RO, Chan KJ et al. Hyperbaric oxygen for acute carbon monoxide
poisoning. New England Journal of Medicine 2002; 347(14):1057–1067.
SPECIFIC TOXINS
3.26 CHLOROQUINE AND HYDROXYCHLOROQUINE
These quinolone-related drugs are the most toxic of the antimalarials
when taken in overdose. Hydroxychloroquine is also used to treat
systemic lupus and rheumatoid arthritis. Overdose produces rapid onset
of hypotension, CNS depression, cardiac conduction defects and
hypokalaemia. Chloroquine is a leading cause of pharmaceutical
215
overdose mortality in many countries where malaria is endemic.
Management is supportive.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
• Ingestion of >10 mg/kg of chloroquine is potentially toxic.
• Serious toxicity and increasing mortality is expected with ingested
doses >30 mg/kg.
• Ingestion of >5 g of chloroquine in adults is usually fatal without
intervention.
• The dose-related risk assessment is less well-defined for
hydroxychloroquine, but appears to be similar to chloroquine.
• Children: ingestion of even one tablet is regarded as potentially
lethal in a child less than 6 years of age.
Toxic mechanism
These drugs have a direct toxic effect on the CNS via effects on voltage-dependent Na+
channels. CNS toxicity is compounded by cerebral hypoperfusion from cardiovascular
effects. Cardiovascular manifestations are related to blocking of multiple inward and
outward membrane currents. Hypotension and cardiogenic shock are due to a direct
cardiodepressant effect. Hypokalaemia is believed to be due to a transport-dependent
mechanism.
Toxicokinetics
Both agents have similar toxicokinetics. Absorption after ingestion is rapid and complete.
They are extensively tissue bound and have a volume of distribution of >50 L/kg. They
are partially metabolised and have prolonged half-lives of several weeks. More than 50%
of chloroquine is excreted unchanged.
CLINICAL FEATURES
Onset of symptoms occurs within 1–2 hours.
Clinical features include:
ERRNVPHGLFRVRUJ
• Non-specific symptoms of dizziness, nausea and vomiting
• Cardiovascular
— Rapid onset of hypotension
— Cardiac conduction defects (QRS widening, QT prolongation)
— Cardiac arrest
— Depressed conscious state
— Seizures
• Metabolic
— Hypokalaemia due to intracellular shift of potassium.
INVESTIGATIONS
SPECIFIC TOXINS

• EUC
— Detect and monitor hypokalaemia
• Serial ECGs
— Detect and monitor QRS and QT prolongation
— Sinus arrest, varying degrees of heart block
• Specific levels are not routinely available and do not assist in
216 management. They may be useful retrospectively to confirm the
diagnosis.
21
6
MANAGEMENT
TOXICOLOGY HANDBOOK

• Chloroquine or hydroxychloroquine overdose is a life-threatening
emergency and is managed in an area equipped for
cardiorespiratory monitoring and resuscitation.
— Coma: prompt intubation and ventilation is indicated at the
first sign of a depressed conscious state
— Broad complex tachycardias: manage aggressively with
intubation, hyperventilation and serum alkalinisation. Give
sodium bicarbonate 1–2 mmol/kg IV for QRS prolongation. Aim
for a pH of 7.5–7.55 (see Chapter 4.25 Sodium bicarbonate)
— Hypotension: initially treat with fluid resuscitation but
vasopressors are often required and adrenaline by titrated IV
infusion is the first-line agent
— Seizures: controlled with intravenous benzodiazepines.
• Ensure normokalaemia. Hypokalaemia should be anticipated, but
avoid aggressive replacement, as total body potassium is not
depleted.
• High-dose diazepam (0.5 mg/kg IV bolus then an infusion of
1 mg/kg IV over 24 hours) post-intubation has been advocated.
Its protective mechanism is unclear.
Decontamination
• Administration of activated charcoal is withheld until the airway is
protected.
ERRNVPHGLFRVRUJ
Antidote
• None available.
• All children suspected of ingesting even one chloroquine or
hydroxychloroquine tablet must be assessed and observed in
hospital.
• Patients who are asymptomatic at 6 hours following ingestion
may be discharged. Discharge should never occur at night.
• Patients with signs of cardiotoxicity or seizures are admitted for
observation and supportive care until all clinical features of
toxicity including sinus tachycardia resolve.
• Admission to ICU is indicated following massive ingestions
SPECIFIC TOXINS
(>30 mg/kg) and for patients manifesting signs of significant
cardiotoxicity.
HANDY TIPS
• Anticipate catastrophic deterioration in any patient presenting
early following chloroquine overdose. Intubate and hyperventilate
at the first sign of cardiotoxicity or clinical deterioration.
• Avoid over-enthusiastic correction of hypokalaemia as total body
potassium is not depleted and excessive administration can lead
to life-threatening hyperkalaemia as toxicity resolves. 217
CONTROVERSY
TOXICOLOGY HANDBOOK
• The mechanism of action of high-dose diazepam infusion in
chloroquine and hydroxychloroquine toxicity is unclear and its
efficacy is unproven.
Presentations
Chloroquine phosphate 155 mg tablets (no longer available in Australia)
Hydroxychloroquine sulfate 200 mg tablets (100) (720) available online
References
Clemessy JL, Favier C, Borron SW et al. Hypokalaemia related to acute chloroquine
ingestion. Lancet 1995; 346(8979):877–880.
Clemessy J-L, Taboulet P, Hoffman JR et al. Treatment of acute chloroquine poisoning:
a 5-year experience. Critical Care Medicine 1996; 24:1189–1195.
Marquardt K, Albertson TE. The treatment of hydroxychloroquine overdose. Journal of
Riou B, Barriot P, Rimailho A et al. Treatment of severe chloroquine poisoning. New
England Journal of Medicine 1988; 318:1–6.
Smith ER, Klein-Schwartz W. Are 1–2 dangerous? Chloroquine and hydroxychloroquine
exposure in toddlers. Journal of Emergency Medicine 2005; 28 (4):437–443.
3.27 CHLORAL HYDRATE

Chloral hydrate is still available for use as a sedative in children
undergoing procedures. It was withdrawn as a sedative-hypnotic for
adults because of its narrow therapeutic index. In overdose it causes
rapid onset of CNS depression and cardiac dysrhythmias and these are
frequently lethal without intervention.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Ingestion of >100 mg/kg, twice the upper limit of therapeutic
dosing, is associated with high risk of coma and life-threatening
cardiac dysrhythmias.
Toxic mechanism
Chloral hydrate has a direct irritant action on mucosal surfaces. The mechanism of
action of the toxic metabolite trichloroethanol (TCE) on the CNS and cardiovascular
system is unclear. Cardiac dysrhythmias are thought to be caused by sensitisation of the
myocardium to circulating catecholamines. Chloral hydrate also decreases myocardial
contractility and shortens the refractory period, which enhances cardiotoxicity.
Toxicokinetics
Chloral hydrate is rapidly absorbed following oral administration. It is then rapidly
SPECIFIC TOXINS
converted to the active metabolite TCE by hepatic alcohol dehydrogenase. TCE is

conjugated with glucuronic acid and excreted in the urine and to a limited extent in the
bile. Chloral hydrate has an elimination half-life of only 4–5 minutes whereas TCE has an
elimination half-life of 8–12 hours after therapeutic doses and up to 35 hours after
overdose.
CLINICAL FEATURES
Chloral hydrate overdose is characterised by rapid (<30 min) onset of
life-threatening CNS and cardiovascular toxicity. Gastrointestinal
218 effects and hypothermia complete the clinical profile.
21
8
— Drowsiness, lightheadedness and ataxia may rapidly progress

to coma and respiratory depression.
TOXICOLOGY HANDBOOK
• Cardiovascular
— Cardiac dysrhythmias
– Multifocal premature ventricular ectopics
– Atrial fibrillation
– Supraventricular tachycardia
– Ventricular tachycardia
– Ventricular fibrillation
– Torsades de pointes
– Asystole
— Hypotension
• Hypothermia
• Gastrointestinal
— Corrosive injury may be associated with gastro-oesophageal
necrosis and even perforation.
— Permanent stricture formation is a potential sequela.
INVESTIGATIONS
• Serial 12-lead ECGs are essential to monitor the effects on clinical
conduction and response to therapy.
• Other investigations may be useful to exclude alternative
aetiologies when the diagnosis is in doubt.
• TCE levels can be measured and correlate with toxicity, but
are never available in a clinically useful time frame. They may
ERRNVPHGLFRVRUJ
be useful to retrospectively confirm the diagnosis in forensic
cases.
• Gastroscopy may be indicated after a large ingestion to assess
mucosal damage and potential for stricture formation.
MANAGEMENT
• The patient is initially managed in an area equipped for
• Attention to airway, breathing and circulation are paramount and
managed along conventional lines, as outlined in Chapter 1.2:
Resuscitation.
• Immediate endotracheal intubation and ventilation is indicated at
the first signs of progressive CNS or cardiovascular toxicity.
SPECIFIC TOXINS
• Beta-blockers are indicated for chloral hydrate-induced cardiac
tachydysrhythmias. Administer propranolol 0.5–1 mg or
metoprolol 5 mg (0.1 mg/kg in children) by slow IV injection and
repeat after 5 minutes if response inadequate. An esmolol infusion
is prepared at a concentration of 10 mg/mL in 5% dextrose and
commenced at rate of 0.05 mg/kg/minute (20 mL/hour in a 70-kg
adult) and titrated to response.
• Hypotension is managed with IV fluids. Give 10–20 mL/kg of
IV crystalloid as an initial response (see Chapter 2.5: 219
Hypotension).
• Catecholamines are contraindicated for hypotension as they are
dysrhythmogenic in chloral hydrate toxicity.
TOXICOLOGY HANDBOOK
• Corrosive effects of oral chloral hydrate, especially in large
ingestions, may warrant evaluation with upper gastrointestinal
endoscopy within 24 hours.
Decontamination
• Activated charcoal may be given once the airway is secured with
endotracheal intubation, but never takes precedence over
resuscitation and supportive care measures.
• TCE elimination can be enhanced with haemodialysis, but patients
are usually stabilised by the measures described above, rendering
this intervention unnecessary.
Antidotes
• All suspected paediatric ingestions and adult deliberate self-
poisonings require immediate assessment and observation in
hospital.
• All patients should be closely observed with cardiac monitoring in
place for at least 2 hours and until recovery is complete.
• Development of CNS depression requiring intubation, cardiac
dysrhythmias or hypotension is an indication for admission to an
ERRNVPHGLFRVRUJ
HANDY TIPS
• Torsades de pointes has been treated with IV magnesium
and overdrive pacing but rarely responds; beta-blockade is
indicated.
• Consider haemodialysis in patients with refractory cardiac
dysrhythmias and haemodynamic instability.
PITFALLS
• Exacerbation of ventricular dysrhythmias by the administration of
catecholamines during resuscitation.
• Failure to administer beta-blockers to the patient with ventricular
dysrhythmias.
SPECIFIC TOXINS
CONTROVERSIES
• The administration of beta-blockers is based on the premise that
ventricular dysrhythmias arise as a result of sensitisation of the
myocardium to circulating catecholamines. Their efficacy is
supported by clinical experience and multiple favourable case
reports, but has not been evaluated in clinical trials.
• Flumazenil is reported to reverse the CNS depression of chloral
hydrate, but its administration is not recommended. Given the
220 life-threatening nature of the cardiovascular toxicity, early
definitive control of airway and ventilation with endotracheal
22
0
intubation is preferred.
TOXICOLOGY HANDBOOK
Presentations
Chloral hydrate 1 g/10 mL syrup (200 mL)
References
Graham SR, Day RO, Lee R et al. Overdose with chloral hydrate: a pharmacological and
therapeutic review. Medical Journal of Australia 1988; 149:686–688.
Pershad J, Palmisano P, Nichols M. Chloral hydrate: the good and the bad. Pediatric
Emergency Care 1999; 15:432–435.
Sing K, Erickson T, Amitai Y et al. Chloral hydrate toxicity from oral and intravenous
administration. Journal of Toxicology – Clinical Toxicology 1996; 34:101–106.
Zahedi A, Grant MH, Wong DT. Successful treatment of chloral hydrate cardiac toxicity
with propranolol. American Journal of Emergency Medicine 1999; 17(5):490–491.
3.28 CLONIDINE
Clonidine overdose produces varying degrees of CNS depression and
mild cardiovascular effects. Classically, intoxication manifests clinically
with the triad of drowsiness, miosis and bradycardia. Treatment is
supportive.
RISK ASSESSMENT
• Clinical effects correlate poorly with ingested dose. Significant
CNS depression may occur with doses >20 microgram/kg, but
large doses are sometimes tolerated with minor effects.
• Onset of clinical features is rapid, usually within 2 hours of
ingestion and always within 6 hours.
ERRNVPHGLFRVRUJ
• Children: ingestion of 2 tablets is potentially lethal without
supportive care:
— >10 microgram/kg: bradycardia and hypotension
— >20 microgram/kg: respiratory depression or apnoea.
Toxic mechanism
Clonidine is a centrally acting α2-adrenergic agonist. It acts as a sympathoplegic agent,
decreasing central nervous sympathetic outflow. It also increases endothelial nitric oxide
levels and decreases renin activity.
Toxicokinetics
Clonidine is rapidly and completely absorbed with peak concentration and therapeutic
effects occurring within 1–3 hours. Clonidine has a large volume of distribution of
3–6 L/kg. It is metabolised in the liver, but half the ingested dose is eliminated
unchanged in the urine. Elimination half-life is 6–24 hours. Protein binding is
SPECIFIC TOXINS
approximately 20–40%.
CLINICAL FEATURES
• Onset of toxicity is rapid. Transient early hypertension (not usually
clinically significant) is reported in 20–50% of cases.
• Lethargy, miosis, slurred speech and ataxia usually occur within 2
hours, and always within 6 hours. The patient can frequently be
roused with a stimulus, only to become deeply somnolent again
when not disturbed. 221
• Severe intoxication is associated with coma, bradycardia and
hypotension. Sinus bradycardia (rate sometimes as low as 30/
minute) is common and is frequently present without hypotension
TOXICOLOGY HANDBOOK
or signs of decreased end-organ perfusion. Heart block is
reported.
• Hypothermia, respiratory depression and apnoea are reported, but
uncommon.
• Symptoms resolve within 24 hours.
INVESTIGATIONS
• Serial ECGs
MANAGEMENT
• Intubation and ventilation is only required in the most severe
intoxications.
• Bradycardia is common but specific management (e.g. atropine,
catecholamine infusion or pacing) is rarely required and only if
there is hypotension or evidence of decreased end-organ
perfusion.
• Give 10–20 mL/kg of crystalloid IV to patients with symptomatic
hypotension.
ERRNVPHGLFRVRUJ
Decontamination
• Oral activated charcoal is contraindicated because of the risk of
subsequent CNS depression.
Antidotes
• Naloxone inconsistently provides transient reversal of the
CNS and respiratory depression associated with clonidine
intoxication.
• A trial of administration may be warranted as a temporising
measure if airway or breathing is compromised, but definitive
care with intubation and ventilation is more reliable.
SPECIFIC TOXINS
• Administer repeated doses of 0.1 mg IV every 30–60 seconds

up to a total dose of 0.4 mg while supporting airway and
ventilation.
• For further information on the indications, contraindications and
administration see Chapter 4.19: Naloxone.

• Paediatric patients should be observed in hospital following
222 potential accidental exposure.
• Patients who are clinically well without symptoms at 6 hours
22
following ingestion may be discharged. Discharge should never

2
occur at night.
TOXICOLOGY HANDBOOK
• Patients with mild symptoms may be managed supportively in a

ward environment. Discharge is appropriate when the patient is
clinically well, ambulant, passing urine, eating and drinking.
• Patients with significant CNS depression requiring intubation
require admission to an intensive care unit.
HANDY TIPS
• Consider the diagnosis of clonidine ingestion in any small child
who presents with lethargy, bradycardia and miosis.
• Bradycardia is frequently asymptomatic and specific management
is not required.
• Adults who overdose on clonidine are frequently opioid
dependent and use clonidine to ameliorate symptoms of opioid
withdrawal – avoid naloxone in these patients, as it will
exacerbate opioid withdrawal.
PITFALLS
• Failure to recognise the potential lethality of accidental paediatric
ingestion of clonidine.
• Failure to recognise respiratory depression in children, especially
at night.
• Iatrogenic anticholinergic delirium from excessive doses of
atropine administered in response to bradycardia.
CONTROVERSY
• Role of naloxone.
ERRNVPHGLFRVRUJ
Presentations
Clonidine 100 microgram tablets (100)
Clonidine 150 microgram tablets (100)
Clonidine 150 microgram/mL 1 mL ampoules
References
Erickson SJ, Duncan A. Clonidine poisoning – an emerging problem: epidemiology,
clinical features, management and preventative strategies. Journal of Paediatrics and
Child Health 1998; 34(3):280–282.
Fiser DH, Moss MM, Walker W. Critical care for clonidine poisoning in toddlers. Critical
Care Medicine 1990; 18(10):1124–1128.
Seger DL. Clonidine toxicity revisited. Journal of Toxicology – Clinical Toxicology 2002;
40:145–155.
SPECIFIC TOXINS
3.29 CLOZAPINE
Deliberate self-poisoning with this atypical antipsychotic agent is
uncommon because its use is restricted and closely supervised. Coma
may occur and care is supportive.
RISK ASSESSMENT
• A clear dose–response is not defined but the threshold for 223
severe poisoning including coma may be as low as 100 mg in
adults.
• Clinical manifestations of toxicity are more likely to develop in
TOXICOLOGY HANDBOOK
patients who do not normally take clozapine.
• Children: ingestion of a single tablet usually results in symptoms
and prompts referral to hospital for assessment and observation.
Ingestion of >2.5 mg/kg is associated with sedation,
hypersalivation, tachycardia, ataxia and agitation. Extrapyramidal
effects may develop over the following days.
Toxic mechanism
Clozapine is a tricyclic dibenzodiazepine atypical antipsychotic. It is an antagonist at
mesolimbic dopamine (D1 and D2), serotonin (5-HT) and peripheral alpha (α1) receptors.
Compared to other antipsychotic agents in its class, it is a potent antagonist at
muscarinic (M1), histamine (H1) and gamma-aminobutyric acid (GABA) receptors.
Toxicokinetics
Clozapine is rapidly absorbed following oral administration. It is highly protein bound and
has a moderate volume of distribution of 0.5–3 L/kg. Clozapine is metabolised in the liver
by oxidation (cytochrome P450 1A2, 2D6) to metabolites that are excreted in the urine
and faeces. A significant first-pass effect occurs.
CLINICAL FEATURES
• Onset of intoxication is rapid, occurring within 4 hours of
ingestion.
• CNS depression, including coma requiring intubation, may occur
early.
• Lethargy, confusion, sedation, tachycardia and orthostatic
hypotension are common.
• Anticholinergic effects, such as agitation, ileus or urinary retention,
often occur.
ERRNVPHGLFRVRUJ
• Mydriasis and miosis are both described.
• Hypersalivation is characteristic and may be considered
pathognomonic.
• Seizures occur in approximately 5–10% of patients.
• Extrapyramidal effects are more common in children.
• QT prolongation is uncommon.
• Toxicity usually resolves within 24 hours.
INVESTIGATIONS
Specific investigations as required
• Serial ECGs
SPECIFIC TOXINS
— Patients should have a 12-lead ECG at presentation and at

6 hours. If normal, ECG monitoring may cease. If there is
prolongation of the QT >450 ms, monitoring should continue
until the patient is clinically well and ECG changes have
resolved. Torsades de pointes has not been reported.
• Clozapine levels
— These are readily available and although not helpful in
guiding management may be useful to confirm the
224 diagnosis.
22
4
MANAGEMENT
TOXICOLOGY HANDBOOK

• Basic resuscitative measures ensure a good outcome in the vast
• Coma may develop and require rapid-sequence intubation and
ventilation.
• Treat seizures with benzodiazepines, as outlined in Chapter 2.6:
Approach to seizures.
Decontamination
• Activated charcoal is not indicated unless the airway is first
Antidotes
• None available.
• Patients who are clinically well at 6 hours following ingestion are
fit for medical discharge.
ERRNVPHGLFRVRUJ
• Patients who manifest clinical features of intoxication require
admission for appropriate supportive care.
• Parents of small children who have ingested clozapine are
advised that abnormal (extrapyramidal) movements might occur
up to 7 days later.
HANDY TIPS
• Consider the diagnosis of clozapine overdose in a sedated patient
with features of anticholinergic poisoning but small pupils and
prominent hypersalivation.
• Therapeutic use of clozapine is associated with agranulocytosis
and myocarditis. These are not clinical features of acute
poisoning.
SPECIFIC TOXINS
PITFALL
• Failure to recognise and correct urinary retention.
Presentations
Clozapine 25 mg tablets (28, 100)
Clozapine 50 mg tablets (100)
Clozapine 100 mg tablets (28, 100)
Clozapine 200 mg tablets (100)
Clozapine suspension 50 mg/mL 100 mL 225
References
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Clinical
TOXICOLOGY HANDBOOK
Toxicology 2001; 39(1):1–14.
Cobaugh DJ, Erdman AR, Booze LL et al. Atypical antipsychotic medication poisoning;
an evidence based consensus guideline for out-of-hospital medication poisoning.
Isbister GK, Balit CR, Kilham HA. Antipsychotic poisoning in young children: a systematic
review. Drug Safety 2005; 26(11):1029–1044.
Reith D, Monteleone JP, Whyte IM et al. Features and toxicokinetics of clozapine in
overdose. Therapeutic Drug Monitoring 1998; 20(1):92–97.
Trenton A, Currier G, Zwemer F. Fatalities associated with therapeutic use and overdose
of atypical antipsychotics. CNS Drugs 2003; 17(5):307–324.
Wong DC, Curtis LA. Are 1 or 2 dangerous? Clozapine and olanzapine exposure in
toddlers. The Journal of Emergency Medicine 2004; 27:273–277.
3.30 COCAINE
Cocaine has powerful sympathomimetic and local anaesthetic properties.
It is potentially lethal in overdose if severe hyperthermia, hypertension,
myocardial ischaemia or pro-dysrhythmic effects occur.
RISK ASSESSMENT
• Ingestions of >1 g are potentially lethal.
• The toxic dose is highly variable and small doses, particularly in
non-tolerant patients, may result in significant intoxication.
• The presence of hyperthermia, headache, cardiac conduction
abnormalities, focal neurological signs or chest pain heralds
potentially life-threatening complications.
ERRNVPHGLFRVRUJ
TABLE 3.30.1 Dose-related risk assessment: Cocaine
Dose Effect
1–3 mg/kg Safe local anaesthetic dose
20–30 mg Usual dose in a line of cocaine to be snorted
1 g Potentially lethal
• Pregnancy: cocaine is teratogenic and associated with an

increased incidence of miscarriage and fetal demise.
• Lactation: cocaine is excreted in breast milk and can result in
SPECIFIC TOXINS
infant intoxication.
• Children: ingestion is potentially lethal.
Toxic mechanism
Toxicity results from sympathomimetic, vasospastic and sodium channel blocking (local
anaesthetic) effects. Sympathomimetic effects are due to blockade of presynaptic
catecholamine reuptake and can result in vascular dissection, intracranial haemorrhage
and acute cardiomyopathy. Vasospasm and endothelial fissuring result in acute
coronary syndrome. Blockade of myocardial fast sodium channels may result in
226 ventricular dysrhythmias, as occur in tricyclic antidepressant cardiotoxicity. Central
22
nervous system excitation may result in psychomotor acceleration, seizures and

6
hyperthermia.
TOXICOLOGY HANDBOOK
Toxicokinetics
Well absorbed through the mucous membranes of nasopharynx, pulmonary alveolar tree
and gastrointestinal tract. Peak concentrations achieved fastest with IV and inhalational
administration. Bioavailability depends on route (intranasal 25–80%; smoked 60–70%).
Highly lipid soluble, with a volume of distribution of 2 L/kg. Cocaine is rapidly
metabolised by liver and plasma cholinesterases to water-soluble metabolites. Only 1%
of the drug appears unchanged in the urine. Metabolites may persist in the blood and
urine for up to 36 hours. Clinical duration of effect is approximately 60 minutes, with
biological half-lives being reported between 0.5 and 1.5 hours.
CLINICAL FEATURES
Patients may present with symptoms of acute intoxication, medical
complications of abuse or psychiatric sequelae. The onset of
cocaine intoxication is rapid, with major clinical manifestations
occurring within the first hour and usually lasting several hours.
They include:
— Euphoria
— Anxiety, dysphoria, agitation and aggression
— Paranoid psychosis with visual and tactile hallucinations
— Hyperthermia, rigidity and myoclonic movements
— Seizures
• Cardiovascular
— Tachycardia and hypertension may be severe
— Dysrhythmias and cardiac conduction abnormalities
— Acute coronary syndromes—vasospastic and/or thrombotic
— QT prolongation
— Acute pulmonary oedema
ERRNVPHGLFRVRUJ
• Peripheral sympathomimetic
— Hyperthermia
— Muscle fasciculations
— Mydriasis, sweating and tremor.
• Clinical features associated with the following medical
complications:
— Hyperthermia-induced rhabdomyolysis, renal failure and
cerebral oedema
— Aortic and carotid dissection
— Subarachnoid and intracerebral haemorrhage
— Ischaemic colitis
— Pneumothorax
— Pneumomediastinum.
SPECIFIC TOXINS
INVESTIGATIONS
• EUC
— Detect renal failure and hyponatraemia.
• ECG, CK and troponin
— Detect myocardial ischaemia, infarction, acute coronary 227
syndrome, QT prolongation and rhabdomyolysis.
— A Brugada-type pattern of ECG changes (RBBB with ST
elevation in leads V1, V2 and V3) can occur in cocaine
TOXICOLOGY HANDBOOK
intoxication.
— Overall, the sensitivity of ECG for detecting myocardial
infarction is lower in cocaine users.
• Chest X-ray ± CT chest angiogram
— Detect aortic dissection or pulmonary aspiration.
• CT head
— Detect intracranial haemorrhage.
• Note: Decreased mental status or focal neurological signs
prompts exclusion of hypoglycaemia, aortic dissection or
intracranial haemorrhage.
• Note: Serum or urine cocaine levels are not readily available and
do not assist acute management.
MANAGEMENT
• Cocaine intoxication is a life-threatening emergency and is
and resuscitation.
• Clinical features that require immediate intervention
include:
— Cardiac dysrhythmias including ventricular tachycardia
— Hypertension
— Hyperthermia
— Seizures
— Severe agitation.
• Ventricular tachycardia is treated with an IV bolus of 50–100 mmol
sodium bicarbonate. Ventricular dysrhythmias refractory to
ERRNVPHGLFRVRUJ
bicarbonate and defibrillation are treated with lignocaine
1.5 mg/kg IV followed by an infusion of 2 mg/minute.
• Acute coronary syndromes are treated by standard therapies,
with the exception of beta-blockers. This includes aspirin and
nitroglycerin. Thrombolytics are contraindicated in the presence
of severe hypertension, seizures, intracerebral haemorrhage or
aortic dissection.
• Urgent coronary angiography is indicated in the setting of
ST elevation that persists after nitroglycerin and calcium
antagonists.
• Sinus tachycardia and hypertension are treated with titrated
parenteral benzodiazepines.
• Supraventricular tachycardia refractory to benzodiazepine
sedation is treated with verapamil 5 mg IV or adenosine 6–12 mg
SPECIFIC TOXINS
IV. Cardioversion is indicated if unstable.

• Hypertension refractory to benzodiazepine sedation, consider:
— Phentolamine 1 mg IV repeated every 5 minutes
— Titrated vasodilator infusion (sodium nitroprusside or glyceryl
trinitrate).
— Note: Beta-adrenergic blockers are contraindicated.
• Seizures and agitated delirium are managed with 5 mg diazepam
as an IV bolus every 2–5 minutes, repeated until seizures stop or
228 gentle sedation is achieved (see Chapter 2.6: Seizures and
Chapter 2.7: Delirium and agitation).
22
•
8
Hyperthermia:
TOXICOLOGY HANDBOOK

resuscitation.
— Temperature >39.5°C requires rapid external cooling to
prevent multiple organ failure and neurological injury.
Paralysis, intubation and ventilation may be required.
Decontamination
• Gastrointestinal decontamination with activated charcoal is not
indicated except in the specific instance of cocaine body packers
as discussed in Chapter 2.17: Body packers and stuffers.
• Not clinically indicated.
Antidotes
• None available.
• Patients whose intoxication is adequately controlled with
benzodiazepine sedation and have a normal blood pressure and
12-lead ECG may be managed supportively in a ward
environment. They are discharged when clinically well.
• Patients with significant alteration of conscious state,
hyperthermia or ongoing chest pain are admitted to a high-
dependency or intensive care unit.
ERRNVPHGLFRVRUJ
• Cocaine body packers or stuffers must undergo gastrointestinal
decontamination under medical supervision.
HANDY TIPS
• Early control of agitation with IV benzodiazepine sedation calms
the patient, improves tachycardia, hypertension and hyperthermia
and is safe.
• Administration of beta-adrenergic blockers is contraindicated in
the management of cocaine intoxication because it causes
unopposed alpha-receptor stimulation.
• Ongoing chest pain or headache requires further investigation.
• Acute coronary syndrome is managed according to normal
protocols. CT brain scan should be performed prior to
SPECIFIC TOXINS
anticoagulation or angiography if headache is a feature.
PITFALLS
• Failure to adequately sedate the agitated patient with cocaine
intoxication.
• Administration of beta-blockers.
CONTROVERSIES
229
• Despite theoretical concerns, intravenous lignocaine does not
appear to cause cardiovascular or CNS toxicity when used to
treat dysrhythmias in cocaine toxicity.
TOXICOLOGY HANDBOOK
• Indications for coronary angiography and thrombolytic
therapy in cocaine-associated chest pain with ECG
abnormalities.
Presentations
Prescription medications
Cocaine eye drops 15 mL bottles
Illicit cocaine derivatives
Cocaine hydrochloride powder or paste: processed from the alkaloid extracted from
coca leaves, it cannot be smoked as it decomposes at high temperatures.
Cocaine base (crack cocaine) or free-base: created by combining cocaine hydrochloride
with an alkaline substance to render it heat stable.
References
Afonso L, Mohammad T, Thatai D. Crack whips the heart: a review of the
cardiovascular toxicity of cocaine. American Journal of Cardiology 2007;
100(6):1040–1043.
Lange RA, Hillis LD. Cardiovascular complications of cocaine use. New England Journal
of Medicine 2001; 345(5):351–358.
Zimmerman JL. Cocaine intoxication. Critical Care Clinics 2012; 28:517–526.
3.31 COLCHICINE
Colchicine overdose is uncommon but potentially lethal. Toxicity is
characterised by severe gastroenteritis followed by multi-system organ
failure. Aggressive decontamination and supportive care are the
cornerstones of management.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Any intentional ingestion of colchicine is considered potentially
lethal. The doses outlined in Table 3.31.1 are useful in predicting
outcome, although fatalities are reported with acute ingestion of
as little as 0.2 mg/kg.
TABLE 3.31.1 Dose-related risk assessment: Colchicine
Dose Effect
<0.5 mg/kg Gastrointestinal symptoms
0.5–0.8 mg/kg Systemic toxicity including bone marrow

SPECIFIC TOXINS
depression
10% mortality
>0.8 mg/kg Severe poisoning involving cardiovascular

collapse, coagulopathy, acute renal failure
Approaching 100% mortality
230
• Children: ingestion of one or two colchicine tablets is not
problematic. Larger ingestions may cause severe gastrointestinal
23
symptoms and any symptomatic child should be assessed in

0
hospital.
TOXICOLOGY HANDBOOK
Toxic mechanism
Colchicine is a naturally occurring alkaloid. It is found in certain plants, including the
autumn crocus (Colchicum autumnale) and glory lily (Gloriosa superba). It is used in the
treatment of acute gout and has also been advocated in familial Mediterranean fever and
pericarditis. It binds tubulin and prevents microtubule formation, thus inhibiting mitosis,
as well as other essential intracellular processes. Following overdose, tissues with high
cellular turnover (GIT, bone marrow) are preferentially affected.
Toxicokinetics
Colchicine is rapidly absorbed, with peak levels occurring from 0.5 to 2 hours post-
ingestion. Bioavailability is only 45% as a result of extensive first-pass metabolism. It is
extensively tissue bound with a volume of distribution of 2 L/kg. Elimination is by hepatic
metabolism, with an elimination half-life of up to 30 hours following overdose.
CLINICAL FEATURES
Colchicine overdose usually presents with severe gastroenteritis
followed by onset of multi-organ toxicity (if more than 0.5 mg/kg is
ingested) in the second 24 hours (see Table 3.31.2).
INVESTIGATIONS
• Specific colchicine levels are not routinely available.
• Appropriate laboratory and radiological investigations are used to
identify and monitor fluid, electrolyte and acid–base status and
development of organ toxicity as outlined above.
ERRNVPHGLFRVRUJ
TABLE 3.31.2 Clinical progression of severe colchicine toxicity
Time Effect
2–24 hours Nausea, vomiting, diarrhoea, abdominal pain. Severe

GI fluid losses can result in haemodynamic
instability. Peripheral leucocytosis commonly
seen on blood film
2–7 days Bone marrow suppression and pancytopenia,

rhabdomyolysis, renal failure, progressive
metabolic acidosis, respiratory insufficiency,
ARDS, cardiac dysrhythmias and risk of sudden
cardiac death
SPECIFIC TOXINS
>7 days Rebound leucocytosis and transient alopecia.
Complete recovery is expected in patients who
survive to this stage
MANAGEMENT
• Patients may present in hypovolaemic shock due to massive GI 231
fluid losses. They require resuscitation with large volumes of
intravenous crystalloid solutions.
• Aggressive supportive care in an intensive care environment
TOXICOLOGY HANDBOOK
offers the best chance of survival in severe colchicine poisoning.
This includes meticulous management of fluid, electrolyte and
acid–base status and infectious complications.
• Early respiratory insufficiency and cardiac arrest is anticipated;
airway protection and ventilatory assistance are implemented as
necessary.
• Close clinical, physiological and laboratory monitoring is
indicated.
• Patients with severe toxicity require invasive monitoring.
Decontamination
• Administer activated charcoal 50 g (1 g/kg in children) as soon as
possible to any patient who has potentially ingested >0.5 mg/kg
of colchicine, because prevention of absorption of even a small
amount may be life saving.
• Multiple-dose oral activated charcoal may enhance elimination,
but is technically difficult in the vomiting patient. It has not been
shown to affect outcome and is not routinely recommended.
Antidotes
• Colchicine-specific antibodies were used successfully in a single
case of colchicine overdose, but are not currently available.

• All adult cases of deliberate self-poisoning are admitted for
observation.
ERRNVPHGLFRVRUJ
• Patients who do not develop gastrointestinal symptoms within 24
hours of ingestion are medically cleared.
• Patients with significant toxicity require admission to an intensive
care unit.
HANDY TIP
• Admit ALL colchicine overdoses. Arrange early transfer to
intensive care if more than 0.5 mg/kg is ingested or any
symptoms develop.
PITFALLS
• Failure to identify ingestion of colchicine at presentation.
• Failure to anticipate the severity of colchicine poisoning.
SPECIFIC TOXINS
CONTROVERSY
• Utility of granulocyte colony-stimulating factor (GCSF) in the
treatment of severe leucopenia.
Presentations
Colchicine 500 microgram tablets (30)
232 References
Harris R, Gillet M. Colchicine poisoning – overview and new directions. Emergency
23
Medicine 1998; 10:161–167.

2
Jayaprakash V, Ansell G, Galler D. Colchicine overdose: the devil is in the detail. New
TOXICOLOGY HANDBOOK
Zealand Medical Journal 2007; 120(1248):81–88.
3.32 CORROSIVES
Alkalis: Ammonia, Potassium hydroxide, Sodium hydroxide, Sodium
hypochlorite Acids: Hydrochloric acid, Sulfuric acid Other: Glyphosate,
Paraquat, Phenols, Potassium permanganate, Mercuric chloride, Zinc
chloride
Ingestion of corrosive agents causes injury to the upper airway and
gastrointestinal tract. Upper airway injury is a life-threatening
emergency. Endoscopy and CT scanning stratify the risk for delayed
sequelae in symptomatic patients.
RISK ASSESSMENT
• Deliberate or unintentional ingestion of concentrated sulfuric acid
(H2SO4), sodium hydroxide (NaOH) solutions and solid
preparations are associated with severe corrosive injury to the
pharynx, upper airway, oesophagus and stomach. These agents
are not associated with systemic toxicity.
• Stridor, dyspnoea, dysphonia or throat pain indicates airway injury
and an immediate threat to life.
• Significant gastro-oesophageal injury is indicated by any two of
the following: stridor, drooling or vomiting.
• Ingestion of >60 mL of concentrated hydrochloric acid (HCl) leads
to severe injury to the stomach and duodenum with necrosis and
ERRNVPHGLFRVRUJ
perforation, rapid onset of severe multi-organ failure and is
usually fatal.
• Ingestion of <150 mL household bleach containing dilute sodium
hypochlorite does not cause significant corrosive injury.
• The absence of lip or oral burns does not exclude significant
gastro-oesophageal injury.
• The following corrosive agents are also associated with severe
systemic toxicity: glyphosate, mercuric chloride, paraquat,
potassium permanganate, zinc (see Chapter 3.38: Glyphosate
and Chapter 3.63: Paraquat).
• Children: unintentional ingestion of household drain and oven
cleaners or automatic dishwashing powders can cause severe
corrosive injury. Unintentional ingestion of household bleach is
SPECIFIC TOXINS
usually benign. Ingested button batteries may cause local
corrosive injury if they lodge in the oesophagus (see Chapter
3.21: Button batteries).
Toxic mechanism
Corrosive agents cause direct chemical injury to tissues. The extent
of injury is dependent on pH, concentration and volume ingested.
Alkaline agents cause liquefactive necrosis, resulting in deep and
progressive mucosal damage. Acids cause protein denaturation and
coagulative necrosis. 233
CLINICAL FEATURES
TOXICOLOGY HANDBOOK
• Following corrosive ingestion, patients may experience immediate
pain in the mouth and throat, drooling, odynophagia, vomiting and
abdominal pain.
• Laryngeal oedema may cause rapidly progressive stridor,
hoarseness and respiratory distress.
• Oesophageal perforation and mediastinitis are associated with
chest pain, dyspnoea, fever, subcutaneous emphysema and a
pleural rub.
• Thirty per cent of patients with grade IIB or III injury (see below)
will develop oesophageal strictures.
• Grade II and III injuries are associated with oesophageal
carcinoma 40–50 years later.
• Perforation of the stomach or small intestine produces clinical
features of peritonitis.
• Gastrointestinal tract perforation is complicated by septic shock
and multi-organ failure.
• Patients who ingest large amounts of concentrated acids usually
present in shock with profound metabolic acidosis and progress
to multi-organ failure and death despite laparotomy and surgical
debridement of necrotic tissue.
INVESTIGATIONS
All patients with persistent vomiting, oral burns, drooling or abdominal
pain require further investigation to define the extent of injury and
ERRNVPHGLFRVRUJ
define the risk for immediate (perforation) and delayed (stricture)
sequelae. Traditionally, this has been based on endoscopy within
24 hours of ingestion. Recently, CT scanning has been advocated as
an alternative to endoscopy.
• Endoscopic grading
— Grade 0 Normal
— Grade I Mucosal oedema and hyperaemia
— Grade IIA Superficial ulcers, bleeding and exudates
— Grade IIB Deep focal or circumferential ulcers
— Grade IIIA Focal necrosis
— Grade IIIB Extensive necrosis
• CT grading
— Grade 0 Normal appearance of organs
— Grade I Oedematous wall thickening
SPECIFIC TOXINS
— Grade II Grade I and soft tissue infiltration

— Grade III Grade II + air bubbles in organ wall, free
mediastinal or peritoneal air or fluid collection
MANAGEMENT
• Symptomatic corrosive ingestion is a time-critical emergency
managed in an area equipped for resuscitation.
234
• The early potential life threat is rapid onset of upper airway
23
oedema and compromise.

4
• Early endotracheal intubation or surgical airway may be required.

• Do not insert a nasogastric tube until after endoscopy.
TOXICOLOGY HANDBOOK

• Administer analgesia as required.
• The symptomatic patient remains nil by mouth until the extent of
injury is defined by endoscopy or CT scanning.
• Urgent surgical intervention is required if there is evidence of full
thickness necrosis or perforation.
• Broad-spectrum antibiotics are not indicated unless there is
evidence of perforation.
Decontamination
• The mouth may be rinsed with water as an immediate first aid
measure.
• Do not induce vomiting.
• Do not administer oral fluids.
• Do not administer activated charcoal.
• Do not attempt pH neutralisation.
Antidotes
• None available.
• Patients who are asymptomatic and tolerating oral fluids at
4 hours post-ingestion are medically clear for discharge.
ERRNVPHGLFRVRUJ
• Symptomatic patients remain nil by mouth and are admitted for
observation and further investigation within 24 hours. Further
management and disposition is directed by endoscopic
findings.
• Patients with airway compromise require intensive care admission
once the airway is controlled.
• Patients with haemodynamic instability or evidence of
gastrointestinal perforation require urgent surgical intervention and
subsequent intensive care admission.
HANDY TIPS
• Signs and symptoms correlate poorly with the extent of gastro-
oesophageal injury.
•
SPECIFIC TOXINS
Stridor, dysphonia or dysphagia indicates the potential for
imminent airway compromise.
• Absence of oral and lip burns does not exclude significant
gastro-oesophageal injury.
PITFALL
• Delaying endoscopy or CT scanning beyond 24 hours of
injury.
235
CONTROVERSIES
• Relative role of endoscopy and CT scanning to determine extent
of oesophageal injury. CT scanning has recently been advocated
TOXICOLOGY HANDBOOK
as a safer alternative to endoscopy. It may however
underestimate the severity of injury during the early phase. CT
scanning appears to have lower sensitivity and higher specificity
for predicting major outcomes when compared with endoscopy.
CT scanning is indicated where endoscopy cannot be performed
safely.
• There is no evidence that corticosteroids prevent oesophageal
stricture formation following corrosive injury from alkali ingestion,
and they may increase mortality following grade III injury.
Sources
Ammonia – anti-rust products, jewellery and metal cleaners
Hydrochloric acid – metal cleaners
Sodium hydroxide – button batteries, detergents, drain and oven cleaners
Sodium hypochlorite – bleaches and household cleaners
Sulfuric acid – automotive batteries, drain cleaners
References
Lurie Y, Slotky M, Fischer D et al. The role of chest and abdominal computed
tomography in assessing the severity of acute corrosive ingestion. Clinical
Toxicology 2013; 51:834–837.
Munoz EM, Garcia-Domingo MI, Santiago JR et al. Massive necrosis of the
gastrointestinal tract after ingestion of hydrochloric acid. European Journal of
Surgery 2001; 67:195–198.
Pelclová D, Navrátil T. Do corticosteroids prevent oesophageal stricture after corrosive
ingestion? Toxicological Reviews 2005; 24(2):125–129.
Zargar SA, Kochhar R, Nagi B et al. Ingestion of corrosive alkalis: spectrum of injury to
upper gastrointestinal tract and natural history. American Journal of
Gastroenterology 1992; 87(3):337–341.
ERRNVPHGLFRVRUJ
3.33 CYANIDE
Acute cyanide intoxication is rare but dramatic and lethal. Rapid removal
from the source, attention to the principles of critical care and timely
administration of an antidote in selected cases provides the best
opportunity for survival.
RISK ASSESSMENT
• Acute cyanide exposure, whether by ingestion of cyanide salts or
inhalation of hydrogen cyanide gas, is potentially rapidly lethal.
Death is likely to occur before arrival at hospital.
• The lethal oral dose in adults is 50 mg of hydrogen cyanide or
SPECIFIC TOXINS
200 mg of potassium cyanide.

• Patients who arrive alive at hospital following inhalational
exposure survive with supportive care.
• Ingestion of acetonitrile can lead to delayed onset (up to 24
hours) of life-threatening cyanide toxicity.
• Although potentially lethal, amygdalin (cyanogenic-containing
plant material, usually seeds) is rarely ingested in a dose sufficient
to cause serious poisoning.
236
• Chronic occupational intoxication leads to non-specific symptoms
such as headache and fatigue.
23
•
6
Children: unintentional ingestion of cyanide is potentially lethal.

TOXICOLOGY HANDBOOK
Toxic mechanism
Cyanide acts at several sites. It binds to the ferric ion (Fe3+) of cytochrome oxidase and
inhibits oxidative metabolism, leading to lactic acidosis. It stimulates release of biogenic
amines, resulting in pulmonary and coronary vasoconstriction. In the CNS, cyanide
triggers neurotransmitter release, particularly N-methyl-D-aspartate (NMDA), which leads
to seizures.
Toxicokinetics
Cyanide is rapidly absorbed and taken up into cells. It has a volume of distribution of
1.5 L/kg and is protein bound. The metabolism of cyanide is not fully understood. The
main mechanism is thought to involve hepatic transfer of sulfane sulfur to cyanide,
forming thiocyanate, which is non-toxic and excreted in the urine. This reaction is
catalysed by the enzyme rhodanese. Cyanide elimination half-life is 2–3 hours.
Acetonitrile (methyl cyanide), an industrial solvent, undergoes hepatic metabolism in vivo

to yield cyanide. The process takes place slowly with the conversion half-life estimated
to be greater than 30 hours.
CLINICAL FEATURES
• Acute inhalation of hydrogen cyanide gas leads to loss of
consciousness within seconds to minutes.
• Symptoms develop within minutes of ingestion of cyanide salts.
• Early features include nausea, vomiting, headache, dyspnoea,
tachypnoea, hypertension, tachycardia, agitation, collapse and
seizures.
• Progressive features include hypotension, bradycardia, confusion,
tetany, drowsiness, respiratory depression and coma.
• Onset of clinical features of cyanide toxicity may be delayed up to
24 hours following ingestion of acetonitrile.
ERRNVPHGLFRVRUJ
• Delayed neurological toxicity, usually parkinsonism, may be
observed weeks to months after surviving a serious acute
poisoning.
INVESTIGATIONS
• EUC
• Arterial blood gases and serum lactate
— Serum lactate strongly correlates with severity of intoxication.
— In smoke inhalation victims without severe burns, the
sensitivity, specificity and positive predictive value of a serum
SPECIFIC TOXINS
lactate >10 mmol/L for cyanide levels >40 micromol/L
(0.1 mg/dL) are 87%, 94% and 95%, respectively.
• Cyanide levels
— These do not aid acute management but confirm diagnosis in
retrospect.
— Take blood before antidotes are commenced (use a
heparinised tube).
TABLE 3.33.1 Correlation of blood levels and clinical effects: 237

Cyanide
Level Effect
TOXICOLOGY HANDBOOK
>20 micromol/L (0.05 mg/dL) Symptomatic
>40 micromol/L (0.1 mg/dL) Potentially toxic
>100 micromol/L (0.25 mg/dL) Lethal
MANAGEMENT
• Cyanide poisoning poses multiple immediate threats to life: coma,
seizures, shock and profound lactic acidosis.
• Immediate intubation and ventilation with 100% oxygen is
indicated in severe poisoning.
• Resuscitation proceeds along conventional lines, as outlined in
Decontamination
• Removal from the source of hydrogen cyanide gas exposure is
vital.
• Remove clothes and wash skin with soap and water. Clothing
should be bagged.
• Cyanide is rapidly absorbed and the onset of symptoms occurs
within minutes. Resuscitation takes priority over decontamination.
Activated charcoal is contraindicated until the airway has been
secured by endotracheal intubation.
ERRNVPHGLFRVRUJ
Antidotes
• In a patient with suspected cyanide poisoning and serious clinical
effects (altered mental status, seizures, hypotension, significant
metabolic acidosis), administer a cyanide antidote.
• The available antidotes are hydroxocobalamin, thiosulfate and
dicobalt edetate (see Chapter 4.5: Dicobalt edetate, Chapter
4.14: Hydroxocobalamin and Chapter 4.27: Sodium thiosulfate
for administration details).
• Under most circumstances, hydroxocobalamin is the preferred
antidote if available.
SPECIFIC TOXINS

• Patients who are clinically well at 4 hours may be discharged.
• Patients with a history of acetonitrile ingestion must be observed
for at least 24 hours.
• Patients managed supportively who show rapid clinical
improvement, with normal mental status and vital signs, may be
managed in a ward environment.
• Patients with objective evidence of cyanide intoxication require
238 aggressive supportive care, intubation and ventilation and
consideration for antidote treatment.
23
• Patients with severe cyanide intoxication and cardiovascular

8
instability require management in an intensive care setting.

TOXICOLOGY HANDBOOK
HANDY TIPS
• Consider the diagnosis of cyanide poisoning where a sustained
lactic acidosis is noted in the patient presenting following sudden
collapse.
• Despite the presence of effective antidotes, early aggressive
supportive care alone may be sufficient to achieve a good
outcome in most cases.
• The decision to give an antidote must be made before cyanide
levels are available.
PITFALLS
• Failure to recognise cyanide intoxication.
• Inability to immediately access cyanide antidotes.
CONTROVERSY
• The indications and efficacy of cyanide antidotes are not
established.
Sources
Industrial
Cyanide salts are used in metallurgy and ore extraction
Hydrogen cyanide is a fumigant (aeroplanes, buildings, ships)
Nitriles that yield cyanide are used in manufacture of plastics and synthetic fibres
Non-industrial
Cyanide is the product of combustion of natural substances and synthetic material and
therefore commonly produced in fires
Solvent in artificial nail remover
ERRNVPHGLFRVRUJ
Natural
Amygdalin (apple, apricot and peach pips)
Foodstuffs (almonds, cabbage, spinach, tapioca, white lima beans)
Iatrogenic
Chemical warfare agent
Sodium nitroprusside therapy
References
Baud FJ, Barriot P, Toffis V et al. Elevated blood cyanide levels in victims of smoke
inhalation. New England Journal of Medicine 1991; 325:1761–1766.
Braitberg G, Vanderpyl MMJ. Treatment of cyanide poisoning in Australasia. Emergency
Medicine 2000; 12(3):232–240.
Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009;
39(7):541–552.
Reade MC, Davies SR, Morley PT et al. Review article: management of cyanide
SPECIFIC TOXINS
poisoning. Emergency Medicine Australasia 2012; 24:225–238.
3.34 DIGOXIN: ACUTE OVERDOSE

See also 3.35: Digoxin: Chronic poisoning.
Acute digoxin toxicity manifests with early onset of vomiting and
hyperkalaemia and can progress to life-threatening cardiac dysrhythmias 239
and cardiovascular collapse. Cardiovascular complications are refractory
to conventional resuscitation measures. Digoxin immune Fab is a highly
effective antidote.
TOXICOLOGY HANDBOOK
RISK ASSESSMENT
• Acute digoxin intoxication occurs if more than 10 times the daily
defined dose is ingested.
• Potentially lethal digoxin intoxication is predicted by:
— Dose ingested >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/L (12 ng/mL) at any time
— Serum potassium >5.5 mmol/L.
• Potentially lethal natural cardiac glycoside intoxication can occur
following ingestion of certain plants or plant parts, or of
concoctions or teas brewed using glycoside-containing plants or
toad skins.
• Children: ingestion of up to 75 microgram/kg is safe and does
not require hospital observation or treatment unless symptoms
develop.
Toxic mechanism
Digoxin inhibits the membrane Na+–K+-ATPase pump, leading to a reduced sodium
gradient and reduced calcium extrusion from the cell. This results in increased
concentrations of intracellular calcium (enhanced automaticity, positive inotropic effect)
and extracellular potassium. Digoxin also enhances vagal tone, resulting in decreased
sinoatrial and atrioventricular node (AV) conduction velocities.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak
effects usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg). Digoxin
undergoes minimal hepatic metabolism and is eliminated unchanged by the kidneys. The
elimination half-life is 30–40 hours and prolonged further in renal impairment.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
Nausea and vomiting are early clinical features of acute digoxin
poisoning and develop within 2–4 hours of ingestion. Peak serum
digoxin levels are reached at approximately 6 hours and death
secondary to cardiovascular collapse may follow at 8–12 hours.
Specific clinical features include:
— Nausea, vomiting and abdominal pain
• Cardiovascular
— Bradycardias
– First, second or third degree AV block
– AF with ventricular response <60
— Increased automaticity
SPECIFIC TOXINS
– Ventricular ectopic beats or bigeminy

– Supraventricular tachycardia with AV block
— Hypotension
— Lethargy
— Confusion and delirium.
• Note: Acute natural cardiac glycoside intoxication has similar
clinical features. However, onset may be more rapid if liquid
240
preparations are ingested.
24
0
INVESTIGATIONS
TOXICOLOGY HANDBOOK

• Serum digoxin levels
— Confirm poisoning.
— Provide indication for antibody treatment.
— Perform level 4 hours post-ingestion and then every 2 hours
until definitive treatment or toxicity resolving.
• EUC
— Hyperkalaemia of any magnitude is an important early sign of
severe digoxin toxicity.
— Assess renal function.
— Essential to monitor progression or resolution of cardiotoxicity.
MANAGEMENT
• Acute digoxin poisoning is a potentially life-threatening emergency
and resuscitation. Cardiac monitoring must be continued until
reversal of toxicity with digoxin immune Fab.
• Potential early life threats that require immediate intervention
include:
— Hypotension
— Cardiac arrest.
ERRNVPHGLFRVRUJ
• In cardiac arrest, standard resuscitation measures are futile.
Advanced cardiac life support is initiated while 20 ampoules (or
as many as are available) of digoxin immune Fab are sourced and
administered. This may be life-saving. Attempts at resuscitation
should continue for at least 30 minutes after the administration of
digoxin immune Fab.
• If digoxin immune Fab is not immediately available,
temporising measures are instituted to deal with imminent
life threats:
— Hyperkalaemia
– Administer sodium bicarbonate 100 mEq IV bolus
(1 mEq/kg in children).
– Give insulin 10 units and 50 mL 50% dextrose
simultaneously as an IV bolus (0.1 units/kg insulin and
SPECIFIC TOXINS
2 mL/kg 10% dextrose in children).
– Note: Calcium is contraindicated.
— Atrioventricular block
– Give atropine 0.6 mg IV bolus. Repeat until desired
clinical effect is achieved to a maximum of 1.8 mg
(20 microgram/kg/dose in children).
– External pacing is rarely effective.
— Ventricular tachydysrhythmias
– Administer lignocaine 1 mg/kg (max 100 mg) IV over 241
2 minutes.
Decontamination
TOXICOLOGY HANDBOOK
• Oral activated charcoal should be offered to cooperative adults
who present within the first hour following overdose. Activated
charcoal alone is unlikely to be life-saving. Administration may be
problematic due to persistent vomiting.
Antidote
• Digoxin immune Fab is the definitive treatment for acute digoxin
poisoning. It is indicated whenever potentially life-threatening
toxicity is predicted or present:
— Cardiac arrest
— Life-threatening cardiac dysrhythmia
— Ingested dose >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/mL (12 ng/mL)
— Serum potassium >5 mmol/L.
• Digoxin immune Fab dosing is empirical or based on the dose
of digoxin known to be ingested (see Chapter 4.6: Digoxin
immune Fab).

• Patients with falling serial serum digoxin levels, normal serum
potassium, no gastrointestinal symptoms and no evidence of
cardiotoxicity at 6 hours do not require further medical care or
observation.
• Patients who have received digoxin immune Fab, have normal
serum potassium, manifest no significant cardiac dysrhythmia and
ERRNVPHGLFRVRUJ
remain clinically well over the next 24 hours do not require further
medical care or observation.
HANDY TIPS
• Early accurate risk assessment allows administration of digoxin
immune Fab before life-threatening toxicity develops.
• If digoxin immune Fab is not immediately available, it is usually
quicker and safer to arrange for it to be transported to the patient
rather than for the patient to be transported to a hospital with
antidote stocks.
• Serum K >5.5 mmol/L predicts 100% mortality without digoxin
immune Fab.
• Calcium is contraindicated in the treatment of digoxin or cardiac
SPECIFIC TOXINS
glycoside-induced hyperkalaemia.
• Digoxin is sometimes co-ingested with other cardiotropic
medications, such as calcium channel blockers. The aetiology of
bradycardia or AV block may not be clear. Therapeutic trial of
digoxin immune Fab may assist risk assessment.
• Do not repeat digoxin levels following administration of digoxin
immune Fab; most laboratories measure both bound and
unbound digoxin, resulting in alarmingly high serum levels that are
of no clinical relevance.
242 • Serum digoxin levels are an unreliable indication of dose following
24
ingestion of natural cardiac glycosides.

2
TOXICOLOGY HANDBOOK
PITFALL
• Failure to stock sufficient digoxin immune Fab. In a large overdose,
antidote needs to be gathered from all available sources.
CONTROVERSIES
• Dose of digoxin immune Fab. Less than the currently
recommended initial doses may be sufficient to reverse toxicity.
Further monitoring and supplementary doses according to
response are necessary if this approach is adopted.
• Multiple-dose activated charcoal may be associated with
improved outcomes in plant glycoside poisoning, particularly
where digoxin immune Fab is not immediately available.
Presentations
Digoxin 62.5 microgram tablets (200)
Digoxin 250 microgram tablets (100)
Digoxin 50 microgram/mL elixir (60 mL)
Digoxin 50 microgram/2 mL ampoules
Note: Natural sources of cardiac glycosides with similar toxicity:
•
Plants: foxglove, lily of the valley, oleander, rhododendron
•
Animals: toad (Bufo spp.) venom and body parts – used in some
traditional Chinese medicines.
References
Antman EM, Wenger TL, Butler VP et al. Treatment of 150 cases of life-threatening
digitalis intoxication with digoxin-specific Fab antibody fragments: final report of a
multicenter study. Circulation 1990; 81(6):1744–1752.
ERRNVPHGLFRVRUJ
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological
Reviews 2004: 23(3):135–143.
De Silva HA, Fonseka MM, Pathmeswaran A et al. Multiple-dose activated charcoal for
treatment of yellow oleander poisoning: a single-blind, randomised, placebo-
controlled trial. Lancet 2003; 361:1935–1938.
Eddleston M, Rajapakse S, Rajakanthan JS et al. Anti-digoxin Fab fragments in
cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial.
Lancet 2000; 355(9208):967–972.
Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for
severe digitalis intoxication in children. New England Journal of Medicine 1992;
326:1739–1744.
3.35 DIGOXIN: CHRONIC POISONING
SPECIFIC TOXINS
See also 3.34: Digoxin: Acute overdose.
Chronic digoxin poisoning is an underdiagnosed condition that carries
significant morbidity and mortality. Digoxin has a narrow therapeutic
index and intoxication commonly develops in elderly patients with
multiple co-morbidities. Use of digoxin immune Fab reduces mortality
and may reduce hospital length of stay and cost of care.
RISK ASSESSMENT 243

• Chronic digoxin poisoning, although variable in severity, is a
life-threatening condition.
• Untreated, mortality within a week is 15–30%.
TOXICOLOGY HANDBOOK
• The probability of digoxin intoxication is predicted by considering
serum digoxin level and clinical features (see Table 3.35.1).
TABLE 3.35.1 Probability of digoxin toxicity
Serum digoxin level Serum digoxin level

1.5 ng/mL 2.5 ng/mL
Clinical features (1.9 nmol/L) (3.2 nmol/L)
Bradycardia only 10% 50%
GI symptoms only 25% 60%
GI symptoms and 60% 90%

bradycardia
Automaticity alone 70% 90%
Automaticity plus >80% 100%

any other feature
Adapted from Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level and
clinical manifestations as determinants in the diagnosis of digoxin
toxicity. Therapeutic Drug Monitoring 2000; 22(2):163–168.
Toxic mechanism
Digoxin inhibits the membrane Na+–K+-ATPase pump, which in turn leads to increased
intracellular calcium (enhanced automaticity, positive inotropic effect) and increased
ERRNVPHGLFRVRUJ
extracellular potassium. Digoxin also enhances vagal tone leading to a decrease in
sinoatrial and atrioventicular (AV) node conduction velocity.
Toxicokinetics
Digoxin is well absorbed after oral administration, with bioavailability 60–80%. Peak
effects usually occur after 6 hours. Its volume of distribution is large (5–10 L/kg).
Digoxin undergoes minimal hepatic metabolism and is eliminated unchanged by the
kidneys. The elimination half-life is 30–40 hours and prolonged further in renal
impairment.
CLINICAL FEATURES
The clinical manifestations of chronic digoxin toxicity are non-specific.
Digoxin intoxication commonly develops in elderly patients in the
context of intercurrent illness, particularly where this leads to
SPECIFIC TOXINS
impaired renal function and digoxin elimination. It is often difficult to

determine whether the unwell patient with an elevated serum digoxin
level has digoxin toxicity or another cause for the observed clinical
features.
Onset is insidious over days or weeks. Clinical features include:
• Cardiovascular
— Bradycardias
– First, second or third degree AV block
– AF with slow ventricular response (<60/minute)
244 — Increased automaticity
– Ventricular ectopic beats or bigeminy
24
4
– Supraventricular tachycardia with AV block

TOXICOLOGY HANDBOOK
— Hypotension
— Syncope
— Nausea, vomiting, abdominal pain
— Often less prominent than in acute toxicity
— Lethargy
— Confusion and delirium
• Visual
— Decreased visual acuity
— Aberration of colour vision (chromatopsia)
— Yellow haloes (xanthopsia).
INVESTIGATIONS
• Serum digoxin level
— The diagnosis of chronic digoxin intoxication is based on a
steady-state level 6 or more hours after the last dose.
— Serum digoxin levels near the therapeutic range of
0.5–1.0 ng/mL (0.6–1.3 nmol/L), correlate poorly with
severity of intoxication (see Table 3.35.1).
• Other investigations
— EUC.
— Investigations as indicated to assess intercurrent illnesses.
ERRNVPHGLFRVRUJ
MANAGEMENT
• Chronic digoxin poisoning is a potentially life-threatening
monitoring and resuscitation. Cardiac monitoring continues until
reversal of toxicity with digoxin immune Fab.
include:
— Hypotension
— Cardiac dysrhythmias
— Cardiac arrest.
• In cardiac arrest, standard resuscitation measures are futile.
Advanced cardiac life support is initiated while 5 ampoules (or as
SPECIFIC TOXINS
many as are available) of digoxin immune Fab are sourced and
administered. This may be life-saving.
• If digoxin immune Fab is not immediately available, temporising
measures are instituted to deal with imminent life threats.
— Hyperkalaemia
– Administer sodium bicarbonate 100 mEq IV bolus
(1 mEq/kg in children).
– Give insulin 10 units and 50 mL 50% dextrose
simultaneously as an IV bolus (0.1 units/kg insulin and
245
5 mL/kg 10% dextrose in children).
– Note: Calcium is contraindicated.
— Atrioventricular block
TOXICOLOGY HANDBOOK
– Give atropine 0.6 mg IV bolus. Repeat until desired
clinical effect is achieved to a maximum of 1.8 mg (20
microgram/kg/dose in children).
– External pacing is rarely effective.
— Ventricular tachydysrhythmias
– Administer lignocaine 1 mg/kg (max 100 mg) IV over
2 minutes.
• Discontinue digoxin.
• Correct hypovolaemia if present.
• Correct hypokalaemia if present.
• Assess and manage contributing intercurrent illnesses.
Decontamination
• Not indicated.
Antidotes
• Digoxin immune Fab is indicated whenever clinical features of
digoxin intoxication are associated with an elevated steady-state
serum digoxin level. A dose of 1–2 ampoules is usually sufficient
to reverse all features of toxicity within 12 hours (see Chapter
4.6: Digoxin immune Fab).

• If significant cardiac dysrhythmias do not occur over a 6-hour
observation period following treatment with digoxin immune Fab,
further cardiac monitoring is not indicated.
ERRNVPHGLFRVRUJ
• The vast majority of patients with chronic digoxin poisoning
require admission to hospital for management of intercurrent
illnesses, even after treatment with digoxin immune Fab.
HANDY TIPS
• Consider the diagnosis of chronic digoxin intoxication in any
patient on digoxin who presents with collapse, hypotension,
bradycardia, dysrhythmia, gastrointestinal complaints, altered
mental status or general deterioration.
• Early treatment with digoxin immune Fab decreases mortality.
• Early treatment with digoxin immune Fab is cost effective
because it eliminates the need for prolonged cardiac monitoring
and decreases hospital length of stay.
•
SPECIFIC TOXINS
In the absence of a serum digoxin level, patients with suspected

chronic digoxin intoxication are safely treated with an initial
empirical dose of 2 ampoules of digoxin-immune Fab.
• If cardiac dysrhythmia or hypotension continue 12 hours after a
definitive dose of digoxin immune Fab, an alternative cause is
likely.
PITFALLS
246
• Failure to appreciate the life-threatening nature of chronic digoxin
poisoning.
24
• Failure to treat with digoxin immune Fab because of

6
underestimation of potential mortality and concerns about cost.

TOXICOLOGY HANDBOOK
CONTROVERSY
• Precise indications for digoxin immune Fab. The threshold for
antidotal therapy requires a consideration of the risk of
cardiovascular deterioration in an individual patient, and the
clinician’s ability to manage that risk with or without antidotal
therapy.
Presentations
Digoxin 62.5 microgram tablets (200)
Digoxin 250 microgram tablets (100)
Digoxin 50 microgram/mL elixir (60 mL)
References
Abad-Santos F, Carca AJ, Ibanez C et al. Digoxin level and clinical manifestations as
determinants in the diagnosis of digoxin toxicity. Therapeutic Drug Monitoring 2000;
22(2):163–168.
DiDomenico RJ, Walton SM, Sanoski CA et al. Analysis of the use of digoxin immune
Fab for the treatment of non-life-threatening digoxin toxicity. Journal of
Cardiovascular Pharmacology and Therapeutics 2000; 5(2):77–85.
Lapostolle F, Borron SW, Verdier C et al. Digoxin-specific Fab fragments as in single
first-line therapy in digitalis poisoning. Critical Care Medicine 2008; 36:3014–3018.
Marik PE, Fromm L. A case series of hospitalised patients with elevated digoxin levels.
American Journal of Medicine 1998; 105(2):110–115.
ERRNVPHGLFRVRUJ
3.36 DIPHENOXYLATE–ATROPINE
This combination drug causes delayed onset of opioid and
anticholinergic effects when ingested by children, even in small amounts.
RISK ASSESSMENT
• Adults are much less susceptible than children to toxic effects.
• Large ingestions have the potential to cause opioid or
anticholinergic poisoning.
• Children:
— Fatalities are reported after repetitive or incorrect dosing
— Acute ingestion of six or more tablets is associated with
SPECIFIC TOXINS
potentially lethal opioid poisoning
— Acute ingestion of one tablet does not cause significant
symptoms and does not require hospital referral
— Acute ingestion of more than one tablet may cause opioid
and/or anticholinergic poisoning and should be assessed and
observed in hospital.
Toxic mechanism
Combination synthetic opioid (diphenoxylate) and anticholinergic (atropine) preparation
used as adjunctive therapy for acute and chronic diarrhoea. Atropine is added to 247
discourage abuse of this medication. Diphenoxylate and difenoxine are opioid agonists.
Atropine is a competitive antagonist of acetylcholine at muscarinic receptors.
TOXICOLOGY HANDBOOK
Toxicokinetics
Diphenoxylate is rapidly and well absorbed following oral administration. It is rapidly
metabolised to difenoxine, a compound that is 5 times more active than diphenoxylate
and undergoes enterohepatic circulation. Diphenoxylate has a volume of distribution of
3.8 L/kg and an elimination half-life of 2.5 hours. Difenoxine has an elimination half-life of
12 hours. Peak plasma concentrations of both diphenoxylate and difenoxine occur at 2
hours. Atropine is rapidly absorbed following oral administration, with peak plasma levels
occurring at 2 hours. It has a volume of distribution of 2.6 L/kg and an elimination
half-life of 2.4–12.8 hours. The co-administration of atropine in this compound
preparation may slow the absorption of diphenoxylate.
CLINICAL FEATURES
The clinical features are those of opioid intoxication and
• Opioid intoxication
— Decreased level of consciousness
— Respiratory depression
— Miosis
— Note: Opioid effects usually manifest within the first few
hours, but may recur after a period of apparent improvement
for up to 12–24 hours.
• Anticholinergic poisoning
— Delirium, agitation
— Tachycardia, dry skin
— Urinary retention
— Note: Not all patients develop anticholinergic effects. If these
do occur, they may precede or be obscured by the opioid
effects. Occasionally, the anticholinergic effects may
predominate.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
Investigations are performed to assess potential complications as
dictated by the individual risk assessment.
• Exclude alternative diagnoses and assess complications.
MANAGEMENT
• Attention to airway, breathing and circulation is paramount. These
SPECIFIC TOXINS
priorities are managed along conventional lines, as outlined in

Decontamination
• Consider administration of oral activated charcoal to the
248 cooperative alert patient who presents within 2 hours.
24
Decontamination is not necessary to ensure a favourable

8
outcome, but may reduce naloxone requirement and length

of stay.
TOXICOLOGY HANDBOOK
Antidotes
• Naloxone is indicated to reverse clinical manifestations of opioid
intoxication. Repeated doses or an infusion may be necessary
(see Chapter 4.19: Naloxone).

• Children who may have ingested no more than one tablet can be
observed at home.
• Children who may have ingested two or more tablets should be
observed in hospital for a minimum of 12 hours. Discharge should
not occur at night.
• Adults are observed for at least 8 hours following deliberate
self-poisoning.
• Symptomatic patients require admission until clinical
manifestations resolve. This may take up to 48 hours.
PITFALL
• Premature discharge.
Presentations
Diphenoxylate hydrochloride 2.5 mg/atropine sulfate 25 microgram tablets (8, 20, 100)
ERRNVPHGLFRVRUJ
References
McCarron MM, Chalhower KR, Thompson GA. Diphenoxylate–atropine (Lomotil)
overdose in children: an update (report of 8 cases and review of the literature).
Pediatrics 1991; 87(5):694–700.
Thomas TJ, Pauze D, Love JN. Are one or two dangerous? Diphenoxylate–atropine
exposure in toddlers. Journal of Emergency Medicine 2008; 34(1):71–75.
3.37 GAMMA-HYDROXYBUTYRATE (GHB)

Includes GHB precursors: gamma-butyrolactone, 1,4-butanediol.
Slang terms: Cherry meth, Easy lay, Fantasy, G, Gamma-O, G caps,
Georgia homeboy, GHB, GHBers, Grievous bodily harm, G-riffik, Liquid E,
SPECIFIC TOXINS
Liquid Ecstasy, Liquid G, Liquid X, Mils, Scoop, Soap, Somatomax, Water.
When taken in excessive doses, this illicit drug causes rapid onset of
CNS and respiratory depression, myoclonic jerking and bradycardia.
Management of intoxication is supportive. The duration of toxic effects is
short, with complete recovery occurring within 4–8 hours. Gamma-
butyrolactone and 1,4-butanediol are precursor drugs that are rapidly
metabolised to GHB and cause identical toxicity.
249
RISK ASSESSMENT
• GHB is frequently distributed at a strength of 1 g/mL, but dose
estimation is virtually impossible because concentration varies
TOXICOLOGY HANDBOOK
widely and is almost never known.
• Overdose usually occurs because the concentration supplied was
higher than anticipated by the recreational user or the user is
unfamiliar with the drug.
• Standard recreational doses are up to 30 mg/kg.
• Ingestion of >50 mg/kg can cause coma and respiratory
depression.
• Overdose is life threatening without timely support of airway and
ventilation.
• Maximal toxicity is usually evident by the time of arrival at the
emergency department.
• Co-ingestion of ethanol or other CNS depressants increases the
risk of respiratory depression, apnoea and death.
• Children: any ingestion may be associated with rapid onset of
coma and is regarded as potentially fatal.
Toxic mechanism
GHB is a short-chain carboxylic acid that occurs naturally in the brain. It is both a
precursor and metabolite of gamma-aminobutyric acid (GABA) and may be a
neurotransmitter itself. The mechanism of action is unclear. Hypotheses include agonist
activity at GABAB receptors, activity at specific GHB receptors, dopaminergic
modulation, increased acetylcholine and serotonin levels and interaction with
endogenous opioids.
Toxicokinetics
GHB is rapidly absorbed following oral administration with peak plasma concentrations
occurring 25–60 minutes post-ingestion. The presence of food reduces bioavailability.
It has variable distribution. Gamma-butyrolactone (GBL) is rapidly transformed in the
ERRNVPHGLFRVRUJ
liver to GHB. 1,4-butanediol (BD) is metabolised rapidly to GHB by alcohol
dehydrogenase. The presence of alcohol competitively inhibits metabolism and delays
the onset of effect. GHB is rapidly oxidised to carbon dioxide and water with saturable
kinetics. The elimination half-life is usually less than one hour and elimination is complete
within 4–8 hours.
CLINICAL FEATURES
Clinical effects of GHB occur within 20 minutes of ingestion and
peak at 30–60 minutes. Standard recreational doses produce rapid
onset of euphoria and drowsiness, as well as enhanced sexual
desire, performance and orgasm. In overdose, a brief period of
euphoria is followed by rapid onset of coma. The patient can be
roused with an external stimulus, only to become deeply somnolent
again when not disturbed. Sudden recovery of consciousness occurs,
SPECIFIC TOXINS
usually within 2–3 hours. Recovery is characterised by a short period

of agitation or delirium, and vomiting. Complete recovery is expected
within 8 hours.
Deaths are reported and occur from airway obstruction,
pulmonary aspiration or respiratory arrest.
Typical clinical features observed following overdose include:
— CNS depression
250 — Agitation and delirium
— Miosis
25
0
— Myoclonic movements may be noted in rare cases,

sometimes mimicking generalised seizures
TOXICOLOGY HANDBOOK
• Respiratory
— Airway obstruction
— Cheyne–Stokes-type breathing
• Cardiovascular
— Bradycardia
— Mild hypotension responsive to intravenous fluids
— Non-specific ECG changes
• General
— Mild hypothermia
— Vomiting
— Sweating.
Tolerance to GHB develops with regular use and a withdrawal
syndrome is described. Clinical features of GHB withdrawal include
hallucinations, paranoia, insomnia, anxiety, sweating, palpitations and
agitation. Clinical features of withdrawal may develop within 1–12
hours of the last dose of GHB and persist for 3–21 days.
INVESTIGATIONS
• Rarely required, except to exclude alternative diagnoses
for coma.
• Blood and urine GHB levels are not readily available, do not
correlate with toxic symptoms and do not assist management.
ERRNVPHGLFRVRUJ
Serum and urine levels may be useful retrospectively in forensic
cases; however, GHB is rapidly cleared from the blood and may
not be detected in samples taken later in the clinical course. It is
detectable somewhat longer in the urine, but not reliably after
12 hours.
MANAGEMENT
• Acute GHB intoxication is a potentially life-threatening emergency
and resuscitation. Basic resuscitative measures ensure the
survival of the vast majority of patients.
SPECIFIC TOXINS
include:
— Coma
— Loss of airway protective reflexes.
• Bradycardia is common. Specific management (e.g. atropine, 251
catecholamine infusion or pacing) is not usually required.
• Myoclonic movements do not require specific management. If
TOXICOLOGY HANDBOOK
seizures are suspected, they should be managed as outlined in
Chapter 2.6: Seizures.
Decontamination
• Activated charcoal is not indicated because absorption and onset
of CNS depression occurs rapidly.
Antidotes
• None available.
• Patients who are clinically well 2 hours following ingestion may be
discharged. Discharge should not occur at night.
• Patients with mild symptoms are managed supportively in a ward
environment. They are fit for medical discharge when ambulant,
passing urine, eating and drinking.
• Patients with significant CNS depression requiring intubation are
admitted to an intensive care unit. Short-term ventilation in the
emergency department is an alternative when the diagnosis is
certain.
HANDY TIPS
• The resolution of coma may be abrupt. Care is required as
patients may be agitated and forcefully extubate themselves.
ERRNVPHGLFRVRUJ
• The diagnosis of GHB intoxication is frequently made in
retrospect. It should be suspected in any young person found
collapsed in a nightclub, although alternative diagnoses,
particularly alcohol intoxication, are more likely.
• Standard urine toxicological screens do not detect GHB.
PITFALL
• Coma lasting longer than 8 hours suggests an alternative
diagnosis (e.g. co-ingested agent or complication) and should
prompt further investigation.
CONTROVERSY
• Physostigmine has been advocated in the management of GHB
SPECIFIC TOXINS
poisoning. There is no evidence to suggest that the use of

physostigmine confers any additional benefits over supportive
measures alone.
Presentation and Sources

GHB is a white crystalline powder. It is usually distributed dissolved in water
to form a clear colourless liquid. It may be ingested directly or added to
drinks. The concentration is often 1 g/mL but this is extremely variable.
Precursors are found in several household solvents:
252
• Gamma-butyrolactone (GBL) is an oily liquid
25
• Acetone-free nail polish remover pads

2
• 1,4-butanediol (BD) is a water soluble liquid.

TOXICOLOGY HANDBOOK
References
Allen L, Alsalim W. Gamma-hydroxybutyrate overdose and physostigmine. Emergency
Medicine Journal 2006; 23(4):300–301.
Chin RL, Sporer KA, Cullison B et al. Clinical course of gamma-hydroxybutyrate
overdose. Annals of Emergency Medicine 1998; 31:716–722.
Schep LJ, Knudsen K, Slaughter RJ et al. The clinical toxicology of gamma-
hydroxybutyrate, gamma-butyrolactone and 1,4-butanediol. Clinical Toxicology 2012;
50:458–470.
Traub SJ, Nelson LS, Hoffman RS. Physostigmine as treatment for gamma-
hydroxybutyrate toxicity: a review. Journal of Toxicology – Clinical Toxicology 2002;
40(6):781–787.
3.38 GLYPHOSATE
Glyphosate is a widely used herbicide. Severe toxicity occurs as result
of deliberate ingestion of a concentrated formulation. It manifests with
gastrointestinal corrosive symptoms and, in large ingestions, severe
metabolic acidosis, hyperkalaemia and cardiovascular collapse can
occur.
RISK ASSESSMENT
• Ingestion of concentrated formulations poses the greatest risk.
• Dose is frequently difficult to quantify but correlates to severity
(see Table 3.38.1).
• Acute corrosive injury to the upper airways poses an immediate
potential threat to life.
ERRNVPHGLFRVRUJ
TABLE 3.38.1 Dose-related risk assessment: Glyphosate
Dose Effect
<50 mL Asymptomatic or minor gastrointestinal

100% concentrate symptoms
50–150 mL Gastrointestinal symptoms only

100% concentrate
>150 mL Severe gastrointestinal symptoms. Risk of

100% concentrate early upper airways swelling. May develop
multi-system toxicity, especially metabolic
acidosis, hyperkalaemia and hypotension
SPECIFIC TOXINS
>300 mL Potentially fatal. Death usually from refractory
100% concentrate shock
• Tachycardia, abnormal chest X-ray, metabolic acidosis,

hyperkalaemia, acute renal impairment and older age are
associated with poorer prognosis.
• Diluted glyphosate solutions pose little risk when ingested, with
toxicity confined to minor gastrointestinal irritation. 253
• Cutaneous exposures cause skin irritation, but do not cause
systemic toxicity.
•
TOXICOLOGY HANDBOOK
Children: minor ingestions do not need hospital assessment
unless symptoms develop.
Toxic mechanism
Glyphosate (glycine phosphonate) does not inhibit cholinesterase enzymes. Toxicity is
thought to be predominantly due to the surfactant and possibly other co-formulants
rather than glyphosate per se. The mechanism of toxicity is poorly understood but may
involve disruption of cellular membranes and uncoupling of mitochondrial oxidative
phosphorylation. Concentrated glyphosate solutions also cause direct corrosive injury to
the gastrointestinal tract when ingested.
Toxicokinetics
Glyphosate is poorly but rapidly absorbed following ingestion with peak concentrations
occurring within 4 to 6 hours. It is not metabolised, but eliminated unchanged by the
kidneys with an elimination half-life of 4 to 6 hours. The elimination half-life is prolonged
in renal impairment.
CLINICAL FEATURES
— Corrosive injury to the oropharynx, oesophagus, stomach and
duodenum manifests with nausea, vomiting, diarrhoea and
abdominal pain
— Corrosive injury is rarely severe and Grade III injuries (see
Chapter 3.32: Corrosives) are not reported after glyphosate
ingestion
• Cardiovascular
— Myocardial depression
— Hypotension
— Cardiovascular collapse
ERRNVPHGLFRVRUJ
• Respiratory
— Upper respiratory tract irritation and drooling
— Aspiration pneumonitis
— Non-cardiogenic pulmonary oedema has been reported
• Metabolic
— Hyperkalaemia
— Metabolic acidosis
• Patients may develop hepatic and renal dysfunction.
• Multi-organ dysfunction secondary to myocardial depression and
systemic acidosis can also occur.
INVESTIGATIONS
SPECIFIC TOXINS

• Glyphosate levels are not readily available and not clinically
useful
• EUC, LFTs
— Detect and monitor hyperkalaemia.
— Detect and monitor hepatic and renal dysfunction.
• Arterial blood gas, venous lactate
254 — Detect and monitor metabolic acidosis.
• Chest X-ray
25
— Detect aspiration pneumonitis, pulmonary oedema.

4
• Endoscopy/CT chest
TOXICOLOGY HANDBOOK
— This is not routinely required as severe corrosive injury of the

gastrointestinal tract is unusual.
MANAGEMENT
• Manage the patient in an area equipped for cardiorespiratory
• Intubate and ventilate if any evidence of airway compromise from
oropharyngeal corrosive injury.
• Treat hypotension initially with volume replacement. Give a bolus
of 10–20 mL/kg of crystalloid solution IV. Those patients
unresponsive to fluid challenge are likely to require invasive
monitoring and vasopressor therapy.
Decontamination
• Not indicated and technically difficult due to vomiting.
• Haemodialysis enhances the elimination of glyphosate, but is not
generally indicated. It may be useful when the clinical course is
complicated by severe acidosis and acute renal injury.
Antidotes
• None available.
• Patients who are clinically well after 4 hours of observation may
be discharged. Discharge should not occur at night.
ERRNVPHGLFRVRUJ
• Patients with objective evidence of glyphosate intoxication are
admitted to an area with resources and staff available to monitor
fluid balance and observe for potential cardiorespiratory
compromise.
• A patient known to have ingested >150 mL of 100% glyphosate is
admitted to a high-dependency or intensive unit in anticipation of
multiple organ effects within 24 hours.
• Adult patients with dermal occupational exposure do not require
referral to hospital unless they are symptomatic.
HANDY TIP
• Intubate early if stridor develops.
SPECIFIC TOXINS
PITFALLS
• Failure to appreciate potential for cardiovascular compromise
following large ingestions.
• Confusion between glyphosate and organophosphate poisoning.
These are two distinct clinical entities.
CONTROVERSY
• Utility of haemodialysis in severe glyphosate poisoning.
Presentation and Sources 255

Numerous glyphosate formulations are available.
Concentrated preparations are usually 36–50% glyphosate while ready-to-use
diluted preparations are approximately 10%.
TOXICOLOGY HANDBOOK
All preparations also contain polyoxyethyleneamine surfactant.
References
Bradberry SM, Proudfoot AT, Vale JA. Glyphosate poisoning. Toxicological Reviews
2004; 23(3):159–167.
Chen H-H, Lin J-L, Huang W-H et al. Spectrum of corrosive esophageal injury after
intentional paraquat or glyphosate-surfactant herbicide ingestion. International
Journal of General Medicine 2013; 6:677–683.
Lee CH, Shih CP, Hsu KH et al. The early prognostic features of glyphosate-surfactant
intoxication. American Journal of Emergency Medicine 2008; 26:275–281.
Lee HL, Chen KW, Chi CH et al. Clinical presentations and prognostic factors of
glyphosate-surfactant herbicide intoxication: a review of 131 cases. Academic
Roberts DM, Buckley NA, Mohamed F et al. A prospective observational study of the
clinical toxicology of glyphosate-containing herbicides in adults with acute
self-poisoning. Clinical Toxicology 2010; 48:129–136.
3.39 HYDROCARBONS
Aliphatic: Essential oils (includes eucalyptus oil), Kerosene, Petroleum
distillates, Turpentine Aromatic: Benzene, Toluene, Xylene Halogenated:
Carbon tetrachloride, Methylene chloride, Tetrachloroethylene,
Trichloroethylene
See also Chapter 2.16: Solvent abuse.
Hydrocarbons, whether ingested or inhaled, can cause rapid onset of
CNS depression, seizures and (rarely) cardiac dysrhythmias. Aspiration
ERRNVPHGLFRVRUJ
can lead to chemical pneumonitis. Other end-organ effects are
uncommon and usually associated with long-term occupational exposure.
RISK ASSESSMENT
• The major risks following acute ingestion are early CNS
depression and seizures. For most petroleum distillates, more
than 1–2 mL/kg is required to cause significant systemic toxicity.
• Ingestion of as little as 10 mL of eucalyptus oil or other essential
oils may lead to CNS depression and seizures, always within
1–2 hours.
• Ingestion may be complicated by aspiration, resulting in a
pneumonitis that evolves over hours.
• Large or prolonged inhalational exposure may also produce
SPECIFIC TOXINS
asphyxia.
• High-viscosity compounds (motor oil, petroleum jelly) have very
low risk of systemic toxicity or chemical pneumonitis.
• Children:
— There is a small risk of pulmonary aspiration and chemical
pneumonitis following ingestion of any hydrocarbon
— Ingestion of 5 mL of eucalyptus oil or other essential oils is
associated with the rapid onset of coma.
256
Toxic mechanism
25
Disruption of lung surfactant produces a chemical pneumonitis. The mechanism of CNS

6
depression is unclear. Dysrhythmias are secondary to myocardial sensitisation to

TOXICOLOGY HANDBOOK
endogenous catecholamines. Mechanisms of negative inotropic effects are unclear.

Chlorinated hydrocarbons (carbon tetrachloride) are metabolised to produce a
hepatotoxic metabolite.
Toxicokinetics
The hydrocarbons of concern are volatile. Absorption following inhalational exposure is
determined by concentration, duration of exposure and minute ventilation. Absorption
following ingestion is inversely related to the molecular weight of the hydrocarbon.
Minimal absorption occurs following dermal exposure. Distribution to the CNS is
determined by lipid solubility. Most hydrocarbons are eliminated unchanged through
expired air. Some compounds produce metabolites that are excreted in the bile or urine.
CLINICAL FEATURES
• Respiratory
— Immediate coughing and gagging indicates aspiration.
— The development of chemical pneumonitis is heralded by
wheeze, tachypnoea, hypoxia, haemoptysis and pulmonary
oedema. In mild cases, pulmonary signs may be delayed 4–6
hours. Features typically worsen over 24–72 hours and resolve
over 5–7 days.
• Cardiovascular
— Dysrhythmias occur early in poisoning (pre-hospital).
• Neurological
— Profound CNS depression, coma and seizures may occur with
massive acute exposures. Onset is within 2 hours.
— Chronic toluene abuse results in ataxia, dementia and
peripheral neuropathy (see Chapter 2.16: Solvent abuse).
— Nausea and vomiting.
ERRNVPHGLFRVRUJ
• Other
— Chemical phlebitis and local tissue injury occur following IV or
SC injection.
— High-pressure injection injuries can produce extensive tissue
injury involving tendons and deep structures.
— Hepatic and renal injury occurs in carbon tetrachloride (CCl4)
poisoning.
— Toluene is nephrotoxic.
— Benzene is associated with haemolysis and leukaemia.
INVESTIGATIONS
SPECIFIC TOXINS
• Serial ECGs and continuous cardiac monitoring if ectopy or
bigeminy are noted at initial assessment
• FBC, EUC, LFTs, arterial blood gases
• Chest X-ray: radiographic changes lag behind clinical features of
pneumonitis
• Chronic toluene abuse leads to a renal tubular acidosis
characterised by hypokalaemic hyperchloraemic non-anion gap
metabolic acidosis
257
MANAGEMENT
TOXICOLOGY HANDBOOK
• In the event of ventricular dysrhythmias (VT, VF):
— Commence advanced cardiac life support
— Intubate, hyperventilate and correct hypoxia
— Administer propranolol 1 mg IV or metoprolol 5 mg IV
(0.1 mg/kg in children)
— Correct hypokalaemia and hypomagnesaemia
— Withhold catecholamine inotropes if possible.
• Manage seizures along conventional lines, as outlined in Chapter
2.6: Seizures.
• Chemical pneumonitis is managed supportively with supplemental
oxygen and bronchodilators. Non-invasive ventilation or intubation
and ventilation is required in severe cases. Corticosteroids and
prophylactic antibiotics are not indicated.
• Fever is common following significant aspiration with pneumonitis.
Withhold antibiotics until there is objective evidence of pulmonary
sepsis.
Decontamination
• Remove patient from the exposure, remove clothing and wash skin.
• Activated charcoal does not bind hydrocarbons.
• Gastrointestinal decontamination of any kind is contraindicated
following ingestion because induction of vomiting increases the
risk of hydrocarbon aspiration.
ERRNVPHGLFRVRUJ
Antidotes
• None available.
• Children suspected of ingesting small amounts of hydrocarbons
may be observed at home providing they remain asymptomatic.
Any respiratory symptoms beyond an initial cough mandates
hospital assessment and observation.
• Patients who are clinically well without cough, dyspnoea, wheeze
or any alteration in vital signs (including pulse oximetry) at 6 hours
are fit for medical discharge.
SPECIFIC TOXINS
• Patients with any symptoms or alteration in vital signs are

admitted for observation and supportive care.
• Patients with high-pressure injection injuries require surgical
referral for urgent debridement.
HANDY TIP
• Coughing or gagging following ingestion suggests aspiration.
258 PITFALL
• Failure to recognise dry cough as a symptom of evolving
25
8
pneumonitis.
TOXICOLOGY HANDBOOK
CONTROVERSIES
• Mechanisms of myocardial toxicity.
• Chronic occupational solvent encephalopathy.
Sources
Most commercial hydrocarbon products are mixtures. Hydrocarbons are organic
compounds derived from many sources, including petroleum, plant oils and animal fats.
They are widely used in both commercial and household settings as fuel, lubricants,
paint thinners and solvents.
References
Flanagan RJ, Ruprah M, Meredith TJ et al. An introduction to the toxicology of volatile
substances. Drug Safety 1990; 5(5):359–383.
hydrocarbon abuse: clinical toxicology teaching case from NAACT acute and
intensive care symposium. Clinical Toxicology 2014; 52:141–145.
Tibballs J. Clinical effects and management of eucalyptus oil ingestion in infants and
young children. Medical Journal of Australia 1995; 163(4):177–180.
3.40 HYDROFLUORIC ACID

Hydrofluoric acid (HF) is found in car wheel cleaners, rust removing
solutions and in preparations for glass etching and other industrial
processes. Exposure may be dermal, inhalational, ocular or oral.
Accidental dermal exposure is common. Toxicity ranges from minor
dermal injury to life-threatening systemic complications. Ingestion of HF
is potentially lethal.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Any dermal exposure may lead to delayed severe pain and tissue
injury.
• Inhalational exposure can lead to pulmonary injury.
• Systemic life-threatening fluorosis is associated with ingestion or
extensive dermal exposures:
— Dermal exposure with 100% HF solution to 2.5% body
surface area (BSA)
— Dermal exposure with 70% HF to 8% BSA
— Dermal exposure with 23% HF to 11% BSA
— Ingestion of ≥ 100 mL of low-concentration HF (6%) by an
adult
— Ingestion of any volume of higher concentrations of HF.
SPECIFIC TOXINS
• Children: any ingestion of a HF-containing product is potentially
lethal.
Toxic mechanism
Fluoride ions bind directly with calcium and magnesium, as well as interfering with
cellular potassium channels to cause cell dysfunction and death. Systemic toxicity and
ventricular dysrhythmias are secondary to hypocalcaemia, hyperkalaemia,
hypomagnesaemia and acidosis.
Toxicokinetics 259
Hydrofluoric acid is readily absorbed after ingestion or dermal contact. It penetrates
deeply into tissues to release fluoride ions.
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
• Dermal exposure
— Skin contact with HF in concentrations <50% is not
immediately painful and may go unnoticed for several
hours.
— Gradual onset of severe deep unremitting pain develops at
the contact site over hours without obvious erythema or
blistering.
— Pallor and blanching appear after several hours.
— Blistering or tissue loss is delayed many hours or days.
— Pain usually lasts less than 24–36 hours.
— Very large exposures result in systemic fluorosis.
• Inhalational exposure
— Immediate onset of mucosal irritation followed by delayed
onset of dyspnoea, cough and wheeze.
— Non-cardiac pulmonary oedema occurs in severe cases.
• Ingestion
— Low concentrations (<20%) are minimally corrosive to the
gastrointestinal tract.
— Patients may experience vomiting, mild throat pain, dysphagia
and abdominal pain.
— Cardiac arrest from systemic fluorosis may occur without
warning 30 minutes to 6 hours post-ingestion.
• Systemic effects (fluorosis)
— Hypocalcaemia and hypomagnesaemia manifest as tetany
and QT prolongation.
— Ventricular dysrhythmias and cardiac arrest.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• Serial ECGs
— Indicated in all patients with potential systemic HF poisoning
every 2 hours until cardiac monitoring ceases.
— Degree of QT prolongation is a useful marker of hypocalcaemia.
• Serum or ionised calcium and magnesium
— Measure at presentation and at 4 hours in all patients with
potential systemic HF poisoning until cardiac monitoring
ceases.
• Endoscopy
SPECIFIC TOXINS
— May be indicated to assess the extent of corrosive injury, but

only once the patient is stable.
MANAGEMENT
• Systemic HF poisoning is a time-critical emergency and the
patient at risk of this complication is managed in an area
260 equipped for cardiopulmonary monitoring and resuscitation.
• Intravenous calcium is drawn up and available at the bedside.
26
• In the event of ventricular dysrhythmias:

0
— Commence advanced cardiac life support

TOXICOLOGY HANDBOOK
— Intubate and hyperventilate

— Administer calcium gluconate 10% 60 mL (0.6–1.0 mL/kg in
children) or calcium chloride 10% 20 mL (0.2 mL/kg) IV and
repeat every 5 minutes until return of spontaneous circulation.
Large doses are required and ongoing administration to
maintain serum calcium concentrations may be necessary
— Administer sodium bicarbonate 100 mEq IV (3 mEq/kg in
children)
— Administer magnesium sulfate 10 mmol IV (0.05 mmol/kg in
children)
— Beware drug extravasation.
• Administer oral and parenteral analgesia as required.
• Continuous cardiac monitoring is only indicated if there is
potential for systemic fluorosis.
Decontamination
• Dermal exposure
— Remove clothing.
— Irrigate thoroughly with water.
• Ingestion
— Do not induce vomiting.
• Ocular exposure
— Irrigate thoroughly with water or saline.
ERRNVPHGLFRVRUJ
Antidotes
• Calcium (see Chapter 4.2: Calcium).
— Calcium chloride or calcium gluconate is given by IV infusion
as described above to correct systemic hypocalcaemia.
— Calcium gluconate gel is indicated for all symptomatic
patients following dermal exposure. Administer repeatedly to
all affected areas until pain resolves.
— If pain is refractory, calcium gluconate is administered by
either subcutaneous infiltration, regional intravenous infusion
or intra-arterial infusion as described in Chapter 4.2: Calcium.
— WARNING: Do not give calcium chloride by SC injection,
regional IV infusion or arterial infusion as it will cause tissue
damage.
SPECIFIC TOXINS
• Minor skin exposure to low-concentration preparations may be
managed in the outpatient setting with calcium gluconate gel.
• Patients are instructed to return if pain is not controlled with
repeated applications of gel.
• Outpatient follow-up in a Burns Clinic may be appropriate,
particularly with hand involvement.
• Patients who require calcium administration by regional
intravenous or intra-arterial infusion are not discharged until pain 261
is controlled with simple analgesia.
• All patients at risk of systemic HF poisoning are admitted to an
area capable of detecting and treating cardiovascular collapse.
TOXICOLOGY HANDBOOK
Cardiac monitoring is continued for at least 8 hours post ingestion
or 12 hours after extensive dermal exposure and until serum
calcium and 12-lead ECG are normal without calcium
administration.
HANDY TIPS
• Onset of pain is delayed after dermal HF exposure; the less
concentrated the product, the greater is the delay.
• Patients often present with pain in the evening or night after using
a HF product during the previous day.
• Pain is out of proportion to local signs and frequently requires
parenteral opioids until calcium can be effectively delivered.
• Local anaesthetic techniques are contraindicated, as relief of pain
is used as an end point to determine adequacy of calcium
delivery.
• If not available, 2.5% calcium gluconate gel may be made by
mixing:
— 10 mL calcium gluconate for injection and 30 mL of lubricant
jelly
or
— 3.5 g calcium gluconate powder in 150 mL of lubricant jelly.
• Do not use calcium gluconate to irrigate after ocular exposures
– use normal saline or water.
PITFALLS
• Failure to appreciate the severity of dermal injury due to lack of
local signs.
ERRNVPHGLFRVRUJ
• Administration of calcium chloride by subcutaneous injection,
intravenous regional or intra-arterial routes.
CONTROVERSY
• The role of prophylactic calcium infusion in patients at risk of
systemic HF poisoning.
Presentations
Exists in two forms, aqueous and anhydrous:
• Aqueous HF is available in a wide range of concentrations up to 40%
• Anhydrous form is more concentrated (>50%) and used in industry.
Products for domestic use typically contain 5–12% aqueous HF.
References
SPECIFIC TOXINS
Kao W, Dart RC, Kuffner E et al. Ingestion of concentrated hydrofluoric acid: an insidious
and potentially fatal poisoning. Annals of Emergency Medicine 1999; 34(1):35–41.
Kirkpatrick JR, Burd DAR. An algorithmic approach to the treatment of hydrofluoric acid
burns. Burns 1995; 21:495–499.
Kirkpatrick JR, Enion DS, Burd DAR. Hydrofluoric acid burns: a review. Burns 1995;
21:483–493.
3.41 HYDROGEN PEROXIDE

262
26
Hydrogen peroxide (H2O2) is an oxidising agent with a wide range of

2
domestic and industrial applications. Ingestion of concentrated solution

can cause serious toxicity and death due to corrosive effects, and from
TOXICOLOGY HANDBOOK
gas embolism caused by release of oxygen gas.
RISK ASSESSMENT
• Ingestion of small volumes (<30 mL) of 3% H2O2 causes mild
gastrointestinal irritation only.
• Ingestion of larger volumes of 3% H2O2 causes a more significant
gastrointestinal injury and may result in gas embolism.
• Ingestion of concentrated H2O2 solutions (>10%) causes
potentially life-threatening corrosive injury to the airway and
gastrointestinal tract, and life-threatening venous and arterial gas
embolism.
• Exposure of the eye to concentrated H2O2 solutions (>10%)
causes permanent corneal injury.
• Exposure of the skin to concentrated H2O2 solutions (>10%)
causes local injury.
• Gas embolism can also arise where H2O2 solutions are used
medically to irrigate closed body cavities.
• Children: minor exposures to domestic products containing 3%
H2O2 are unlikely to cause significant injury. Any exposure to
concentrated H2O2 solutions (>10%) or where symptoms develop
is of concern and warrants hospital assessment.
Toxic mechanism
Hydrogen peroxide causes toxicity by three mechanisms: direct corrosive injury, oxygen
gas formation and lipid peroxidation. Hydrogen peroxide is corrosive and exposure can
cause local tissue damage to the skin, mucosal membranes or cornea. Metabolism of
ingested H2O2 liberates large quantities of oxygen. Once the amount of oxygen produced
ERRNVPHGLFRVRUJ
exceeds its maximal solubility in the blood, oxygen bubbles form and venous or arterial
gas embolism may occur. Rapid accumulation of oxygen in closed body cavities can
cause mechanical distension and complications such as rupture of a hollow viscus.
Intravascular foaming may occur and can seriously impede left ventricular output. Direct
cytotoxic effects from lipid peroxidation are also thought to occur.
Toxicokinetics
Following ingestion, H2O2 is readily absorbed through the stomach mucosa and into the
portal venous system. It is then rapidly metabolised, predominantly by catalases within
red cells, to yield oxygen and water; 30 mL of 35% H2O2 solution liberates almost 3.5 L
of oxygen at standard temperature and pressure.
CLINICAL FEATURES
• Ingestion
— Clinical features of corrosive injury include nausea, vomiting,
SPECIFIC TOXINS
haematemesis and foaming at the mouth.
— More severe corrosive injury is manifested by blistering of the
mouth and oropharynx, laryngospasm, stridor, cyanosis and
respiratory arrest.
— Tachycardia, lethargy, confusion, coma, seizures and cardiac
arrest and sudden death within minutes may occur with larger
ingestions of concentrated H2O2 (>10%) solutions.
— Painful gastric distension and belching may occur secondary
to liberation of large volumes of gas in the stomach.
— Cerebral oxygen gas embolism manifests with progressive 263
neurological disturbance.
• Inhalation
TOXICOLOGY HANDBOOK
— Usually produces little more than coughing and transient
dyspnoea.
— Highly concentrated solutions can produce severe irritation.
Coughing and dyspnoea can progress to shock, coma,
seizures and pulmonary oedema.
• Dermal
— Inflammation, blistering and skin necrosis can occur, usually
following exposure to concentrated solutions. Subcutaneous
emphysema may be detected.
• Ocular
— Exposure of the cornea to 3% H2O2 solution produces
immediate onset of stinging, irritation, lacrimation and blurred
vision.
— Subepithelial corneal and conjunctival bubbles may be
observed.
— Exposure to concentrated solutions may produce corneal
ulceration and even perforation.
— Transient injury is reported after insertion of soft contact
lenses stored in 3% H2O2 solution without neutralisation.
INVESTIGATIONS
• EUC, FBE, ABGs.
• Chest and abdominal X-rays may demonstrate perforation or
oxygen gas embolism.
ERRNVPHGLFRVRUJ
• Chest X-ray is also indicated if there is evidence of pulmonary
irritation following inhalational exposure.
• Cerebral CT or MRI scanning is indicated if CNS effects develop
and will demonstrate cerebral gas embolism and infarction.
• Upper gastrointestinal endoscopy is considered if there is
persistent vomiting, haematemesis, significant oral burns,
abdominal pain, dysphagia or stridor and the patient has ingested
a solution of >10% concentration.
MANAGEMENT
• Early aggressive airway management is critical to the survival of
the patient who has ingested concentrated H2O2 solution.
Endotracheal intubation or, rarely, a surgical airway may be
SPECIFIC TOXINS
required for life-threatening laryngeal oedema.

• High-flow oxygen via a tight-fitting mask is administered to all
patients.
• Hyperbaric oxygen therapy is of value in treating cerebral gas
embolism.
• Close cardiorespiratory monitoring is essential for any patient at
264 risk of gas embolism.
26
4

TOXICOLOGY HANDBOOK
Decontamination
• Gastrointestinal decontamination is not indicated due to the rapid
decomposition of H2O2.
• Immediate eye irrigation with copious amounts of water or saline
for at least 15 minutes is indicated after ophthalmic exposure.
• Clothing should be removed and the exposed skin washed with
copious amounts of water following dermal exposure.
• Not useful.
Antidotes
• None available.
• Minor unintentional exposures to 3% solutions in either children
or adults do not require hospital evaluation unless persistent
symptoms develop.
• Any patient who has ingested or inhaled concentrated (>10%)
hydrogen peroxide, or has ongoing symptoms, is admitted for
close observation and monitoring.
• Those patients with evidence of corrosive injury to the airway or
gastrointestinal tract require admission for definitive management.
• Patients in whom arterial or venous gas embolism is suspected
should be referred for consideration of hyperbaric oxygen therapy.
• Patients with eye exposures and any signs or symptoms of
corneal injury should be referred for formal ophthalmological
evaluation.
ERRNVPHGLFRVRUJ
PITFALL
• Premature discharge of a patient with vague neurological signs or
symptoms; this may indicate cerebral gas embolism.
CONTROVERSIES
• Indications for CT scanning. It may be appropriate to scan any
patient with abdominal pain as a means to detect evidence of
both oesophageal injury and portal venous gas embolism.
• Indications for hyperbaric oxygen therapy. It is usually
recommended in any case where venous or arterial gas emboli
are suspected or documented.
Presentations
SPECIFIC TOXINS
Solutions ranging in concentration from 3% to 90% are used in various applications:
• Household products (mostly 3% H2O2): disinfectants, bleaches, fabric stain
removers, contact lens disinfectants, hair dyes, tooth-whitening products
• Industrial products: bleaching agent in paper industry
• Medical products: wound irrigation solutions, sterilising solutions for
ophthalmic and endoscopic instruments.
References
Byrne B, Sherwin R, Courage C et al. Hyperbaric oxygen therapy for systemic gas
embolism after hydrogen peroxide ingestion. Journal of Emergency Medicine 2014; 265
46:171–175.
French LK, Horowitz BZ, McKeown NJ. Hydrogen peroxide ingestion associated with
portal venous gas and treatment with hyperbaric oxygen: a case series and review
TOXICOLOGY HANDBOOK
of the literature. Clinical Toxicology 2010; 48:533–538.
Watt BE, Proudfoot AT, Vale JA. Hydrogen peroxide poisoning. Toxicological Reviews
2004; 23:51–57.
3.42 INSULIN
Deliberate self-administered insulin overdose causes profound and
prolonged hypoglycaemia that may result in life-threatening seizures,
coma and permanent neurological injury.
RISK ASSESSMENT
• Deliberate self-poisoning with insulin by subcutaneous injection
causes life-threatening persistent hypoglycaemia with the risk of
permanent neurological injury if not treated aggressively.
• Hypoglycaemia may last for days; patients require prolonged
periods of close monitoring and treatment.
• The severity and duration of hypoglycaemia is unpredictable, is
not dependent on the insulin preparation administered and
correlates poorly with the dose injected.
• Poor outcome is associated with delayed presentation with
established hypoglycaemic coma. The prognosis is excellent with
early effective glucose replenishment.
Toxic mechanism
Insulin is released from the beta pancreatic islet cells at a low basal rate, which increases
in response to various stimuli. Exogenous insulin is used for the treatment of type 1 and
ERRNVPHGLFRVRUJ
type 2 diabetes mellitus, severe hyperkalaemia and calcium channel blocker overdose.
Insulin stimulates the transfer of glucose, potassium, phosphate and magnesium into
cells. It promotes synthesis and storage of glycogen, protein and triglycerides.
Toxicokinetics
In overdose, the pharmacokinetic properties of insulin change. The duration of action is
extended (days) and does not depend on the type of insulin preparation used. Instead, it
is determined by the slow and erratic release from subcutaneous adipose tissue at the
injection site, in addition to the prolonged clearance of the absorbed insulin. Endogenous
insulin is degraded by the liver (60%) and kidneys (40%).
CLINICAL FEATURES
The clinical features are those of hypoglycaemia. They usually
manifest within 2 hours after administration:
• Autonomic symptoms
SPECIFIC TOXINS

— Diaphoresis
— Tachycardia and palpitations
— Agitation and tremor
— Confusion and visual disturbances
— Seizures
— Hemiplegia
266 — Coma.
• The hyperinsulinaemic state commonly persists for >3 days.
26
• Persistent, untreated hypoglycaemia may cause permanent

6
neurological injury and death.

TOXICOLOGY HANDBOOK
INVESTIGATIONS
• Serial blood glucose levels (BGLs)
— Perform every 15 minutes during the resuscitation phase and
until dextrose infusion requirement has stabilised. Frequency
may be reduced to hourly then 2 hourly after that.
• EUC, serum phosphate and magnesium
— Detect and monitor hypokalaemia, hypophosphataemia and
hypomagnesaemia associated with insulin excess.
• Insulin levels
— Insulin levels are elevated, but do not predict the magnitude
or duration of glucose administration and are not clinically
useful.
— Insulin and C-peptide levels are helpful in the extremely rare
circumstance where it is necessary to exclude an endogenous
hyperinsulinaemic state.
MANAGEMENT
• Insulin overdose is a life-threatening emergency and the patient
should be managed in an area capable of detecting and
managing hypoglycaemia with close clinical and physiological
monitoring.
ERRNVPHGLFRVRUJ
• If symptoms of hypoglycaemia occur or BGL is <4.0 mmol/L
(bedside or laboratory value) administer concentrated IV
glucose:
— Adult
– 50 mL bolus of 50% glucose IV
– Repeat if no immediate clinical improvement
— Child
– 2 mL/kg bolus of 10% glucose IV
– Repeat if no immediate clinical improvement.
• Hyperinsulinaemia as manifested by hypoglycaemia requiring
ongoing exogenous glucose administration. Infusion concentration
and rate are titrated to maintain serum glucose at or just above
the normal range.
• Commence a 10% glucose infusion at 100 mL/hour and monitor
SPECIFIC TOXINS
bedside BGL frequently.
• Any further episodes of symptomatic hypoglycaemia are treated
with an IV bolus of concentrated glucose.
• If the above infusion fails to maintain normoglycaemia, obtain
central venous access and commence a titrated infusion of 25%
or 50% glucose to maintain normoglycaemia (or mild
hyperglycaemia).
• Infusion rates of up to around 150 mL/hour of 50% dextrose may
be required for several days. 267
• Manage asymptomatic hypoglycaemia by increasing the rate of
infusion without bolus therapy.
• Monitor serum potassium and supplement as required to keep in
TOXICOLOGY HANDBOOK
the low-to-normal range (e.g. 20 mmol/hour).
Decontamination
Antidotes
• Glucose as outlined in Chapter 4.12: Glucose.
• Patients who are clinically well with normal BGL at 6 hours
following exposure have not administered a significant insulin
dose and do not require further medical care.
• Confirmed significant deliberate self-poisoning with insulin
requires admission to an intensive care or high-dependency unit
for several days of ongoing exogenous IV glucose administration
via a central line and careful monitoring of BGL and serum
potassium levels.
HANDY TIPS
• Anticipate the need for large ongoing glucose requirement and
insert a central line early so that 50% glucose infusion may
commence.
• Diabetic patients have a diminished counter-regulatory hormonal
response to hypoglycaemia and may require increased glucose
replacement.
ERRNVPHGLFRVRUJ
• Withdrawal of glucose infusion should be gradual and should not
take place at night.
• Monitor patients for 4–6 hours after glucose cessation.
• Excessively prolonged glucose infusions can stimulate
endogenous insulin secretion in non-diabetic patients, resulting in
hyperinsulinaemic state and difficulty withdrawing the glucose
infusion.
• Consider the diagnosis of deliberate insulin overdose in the
diabetic patient with unexplained severe and recurrent
hypoglycaemia or the non-diabetic patient who presents with
profound hypoglycaemia.
• Glucagon is not indicated in the hospital management of
hypoglycaemia.
SPECIFIC TOXINS
PITFALLS
• Failure to anticipate ongoing glucose requirement after initial
hypoglycaemia in a patient with deliberate self-poisoning.
• Attempts to manage with an infusion of 5% glucose solution.
• Over-enthusiastic attempts at early weaning of glucose infusion.
CONTROVERSY
268
• Excision of the insulin injection site has been described, but such
an invasive procedure is not justified.
26
8
Presentations
TOXICOLOGY HANDBOOK
Actrapid preparations (insulin neutral) Humulin 30/70 injection 1000 IU/10 mL

Actrapid 300 IU/3 mL cartridges vials
Actrapid 1000 IU/10 mL vials Hypurin isophane (NPH) preparations
Apidra preparations (insulin glulisine) (insulin isophane (bovine))
Apidra 300 IU/3 mL cartridges Hypurin isophane (NPH) 1000 IU/10 mL
Apidra 1000 IU/10 mL vials vials
Humalog preparations (insulin lispro) Hypurin neutral preparations (insulin
Humalog injection 300 IU/3 mL cartridges neutral (bovine))
Humalog injection 1000 mL/10 mL vials Hypurin neutral 1000 IU/10 mL vials
Humalog Mix 25 preparations (insulin Lantus preparations (insulin glargine)
lispro 25%, insulin protamine 75%) Lantus injection 300 IU/3 mL cartridges
Humalog Mix 25 300 IU/3 mL cartridges Lantus injection 1000 IU/10 mL vials
Humalog Mix 25 1000 IU/10 mL vials Levemir FlexPen preparations (insulin
Humalog Mix 50 preparations (insulin detemir)
lispro 50%, insulin protamine 75%) Levemir FlexPen 300 IU/3 mL cartridges
Humalog Mix 50 300 IU/3 mL cartridges Mixtard preparations (insulin neutral,
Humalog Mix 50 1000 IU/3 mL vials insulin isophane)
Humulin R preparations (insulin Mixtard 30/70 300 IU/3 mL cartridges
neutral) Mixtard 50/50 300 IU/3 mL cartridges
Humulin 300 IU/ 3 mL cartridges NovoMix 30 preparations (insulin aspart
Humulin 1000 IU/10 mL vials 30%, insulin aspart protamine 70%)
Humulin NPH preparations (insulin Novomix 30 300 IU/3 mL cartridges
isophane) Novomix 30 300 IU/1 mL penfill cartridges
Humulin NPH injection 300 IU/1 mL, 3 mL NovoRapid preparations (insulin
cartridges aspart)
Humulin NPH injection 1000 IU/10 mL NovoRapid 300 IU/3 mL cartridges
vials NovoRapid 1000 IU/10 mL vials
Humulin 30/70 preparations (insulin Protaphane preparations (insulin
neutral 30%, insulin isophane 70%) isophane)
Humulin 30/70 injection 300 IU/3 mL Protaphane 1000 IU/10 mL
cartridges Protaphane 300 IU/3 mL
ERRNVPHGLFRVRUJ
References
Haskell RJ, Stapczynski JS. Duration of hypoglycaemia and need for intravenous glucose
following intentional overdoses of insulin. Annals of Emergency Medicine 1984;
13:505–511.
Megarbane B, Deye N, Bloch V et al. Intentional overdose with insulin: prognostic factors
and toxicokinetic/toxicodynamic profiles. Critical Care 2007; 11(5):R115.
3.43 IRON
Ferrous chloride, Ferrous fumarate, Ferrous gluconate, Ferrous
phosphate, Ferrous sulfate, Iron amino acid chelates
Iron poisoning is characterised by both local gastrointestinal and
SPECIFIC TOXINS
dose-related systemic toxicity. Toxicity is determined by the quantity of
elemental iron ingested. Most acute overdoses produce minor or
moderate gastrointestinal effects only. In large overdoses, systemic
toxicity can be prevented by early gastrointestinal decontamination and/
or administration of desferrioxamine.
RISK ASSESSMENT
• Iron overdose is potentially lethal.
269
• Risk assessment is based on the ingested dose of elemental iron
(see Table 3.43.1) and the observed evolving clinical features (see
Table 3.43.2).
• The amount of elemental iron in a ferrous or ferric salt is
TOXICOLOGY HANDBOOK
calculated as follows:
— Ferric chloride dose divided by 3.5
— Ferrous chloride dose divided by 4
— Ferrous fumarate dose divided by 3
— Ferrous gluconate dose divided by 9
— Ferrous sulfate (dried) dose divided by 3.3
— Ferrous sulfate (heptahydrate) dose divided by 5.
• Refinement of the initial risk assessment can be achieved by:
— Abdominal X-ray to confirm or quantify ingestion
— An iron level at 4–6 hours post-ingestion.
• Patients presenting with established systemic iron toxicity have a
poor prognosis and may not respond to medical therapy.
• Children: the dose ingested is usually less than that expected to
cause systemic toxicity (60 mg/kg).
TABLE 3.43.1 Dose-related risk assessment: Iron
Elemental iron dose Effect
<20 mg/kg Asymptomatic
20–60 mg/kg Gastrointestinal symptoms
>60–120 mg/kg Systemic toxicity anticipated
>120 mg/kg Potentially lethal
ERRNVPHGLFRVRUJ
TABLE 3.43.2 Classical stages of severe iron poisoning
Time post-ingestion Clinical features
0–6 hours Direct corrosive effect on GI tract

characterised by vomiting, diarrhoea
and abdominal pain. Fluid losses may
be sufficient to cause hypovolaemic
shock
6–12 hours Progressive increase in iron absorption

and distribution. Some resolution of
symptoms may be observed, giving
false hope of recovery
SPECIFIC TOXINS
12–48 hours Disruption of cellular metabolism

manifested as shock from vasodilation
and third-space losses, anion gap
metabolic acidosis and hepatorenal
failure
2–5 days Acute hepatic failure with jaundice, coma,

hypoglycaemia, coagulopathy and
270 elevated aminotransferases. This
27
phase is rare, but has a high mortality

0
TOXICOLOGY HANDBOOK
2–6 weeks Delayed sequelae, including cirrhotic liver

disease and GI fibrosis/strictures
Toxic mechanism
Local
Direct corrosive effect on the gastrointestinal (GI) mucosa manifests with symptoms
ranging from vomiting and diarrhoea to haematemesis and melaena. Large GI fluid
losses may contribute to significant hypovolaemia. Systemic toxicity does not occur in
the absence of GI symptoms.
Systemic
Iron acts as a direct cellular toxin via poorly understood mechanisms. The chief target
organs are the cardiovascular system and the liver. CNS toxicity is secondary to
cardiovascular instability and metabolic derangements. Severe metabolic acidosis is
observed following large overdoses and attributed to lactic acid formation and the
liberation of hydrogen ions from the hydration of free ferric ions in the plasma.
Coagulopathy is frequently observed and attributed to interference with the coagulation
cascade.
Toxicokinetics
Absorption of iron from the GI tract is normally finely regulated according to the
requirements of the body. In overdose these mechanisms are overwhelmed and the
bioavailability of iron increases significantly. Absorbed iron shifts intracellularly over a
period of hours. Elimination is minimal under normal conditions.
CLINICAL FEATURES
Iron toxicity is classically described as having five stages (see
Table 3.43.2), although this is an over-simplification. Not all patients
ERRNVPHGLFRVRUJ
experience all stages and the duration of each stage is imprecise and
they usually overlap. Iron toxicity is more accurately conceptualised
as two overlapping stages with a pathophysiological basis:
gastrointestinal and systemic toxicity.
INVESTIGATIONS
• Serum iron concentration:
— Iron levels usually peak at 4–6 hours following ingestion.
Following this there is rapid intracellular migration of iron. A
clear correlation between iron levels and clinical toxicity is not
SPECIFIC TOXINS
established, but peak levels >90 micromol/L (500 microgram/
dL) are thought to be predictive of systemic toxicity.
• Arterial or venous blood gas
— An anion gap metabolic acidosis is a useful marker of
systemic toxicity.
• Abdominal X-ray
— Useful in confirming ingestion, and planning and monitoring
decontamination.
• Note: Hyperglycaemia and elevated white cell counts are 271
frequently observed in iron poisoning, but do not correlate with
toxicity.
TOXICOLOGY HANDBOOK
MANAGEMENT
• An early priority is the restoration of adequate circulating volume.
Give boluses of 10–20 mL/kg of crystalloid and assess response.
• Ongoing fluid replacement is essential in the face of continuing
gastrointestinal and third-space losses.
Decontamination
• Iron is not adsorbed to activated charcoal.
• Whole bowel irrigation (WBI) is the decontamination method of
choice and recommended for ingestions >60 mg/kg confirmed on
X-ray (see Chapter 1.6: Gastrointestinal decontamination).
• Surgical or endoscopic removal may be considered in potentially
lethal ingestions if WBI fails or is impractical.
Antidotes
• Desferrioxamine chelation therapy is indicated if systemic
toxicity (shock, metabolic acidosis, altered mental status) is
present or predicted by a serum iron level >90 micromol/L
(500 microgram/dL) at 4–6 hours post ingestion. For further
details see Chapter 4.4: Desferrioxamine.

• Children thought to have ingested <40 mg/kg may be managed at
home provided they remain asymptomatic. Larger or symptomatic
ERRNVPHGLFRVRUJ
ingestions are evaluated in hospital. The child who remains
asymptomatic at 6 hours and has an abdominal X-ray negative for
iron may be safely discharged.
• All adults who have deliberately self-poisoned with iron are
evaluated in hospital. If the history suggests ingestion of
<60 mg/kg of iron and they remain asymptomatic at 6 hours,
further medical observation is unnecessary.
• Symptomatic patients requiring intravenous fluid therapy or WBI
require admission to hospital.
• Those presenting with established systemic iron toxicity or
requiring intravenous chelation therapy are admitted to
intensive care.
SPECIFIC TOXINS
HANDY TIPS
• Where serum iron levels are not readily available, a fall in serum
bicarbonate concentration is a good surrogate marker of systemic
iron poisoning and, in conjunction with worsening clinical features,
would justify desferrioxamine administration.
• Iron supplements are readily accessible to pregnant women and
thus are frequently taken in overdose. The fetus is relatively
protected unless maternal cardiovascular instability develops.
Therapy is directed towards care of the mother and does not
272 differ from the care of the non-pregnant patient.
27
2
PITFALLS
• Over-treatment of trivial ingestions.
TOXICOLOGY HANDBOOK
• Failure to perform initial risk assessment thus leading to delays in

therapy and irreversible toxicity following large overdoses.
• Failure to recognise systemic iron toxicity in the patient who
presents late with minimal elevation in serum iron level.
CONTROVERSIES
• Threshold serum iron level that mandates chelation with
desferrioxamine.
• Duration and endpoints for desferrioxamine therapy.
Presentations
There are numerous over-the-counter vitamin preparations containing relatively small
amounts of elemental iron, usually iron amino acid chelates, ferrous phosphate or
ferrous fumarate. The important preparations containing large amounts of elemental
iron are:
Ferrous sulfate 325 mg (105 mg elemental iron) slow-release tablets (30)
Ferrous sulfate 250 mg (80 mg elemental iron)/folic acid 300 mg combination
controlled-release tablets (30)
Ferrous sulfate 6 mg/mL oral liquid (250 mL)
References
Chyka PA, Butler AY. Assessment of acute iron poisoning by laboratory and clinical
observations. American Journal of Emergency Medicine 1993: 11(2):99–103.
Pearn J, Nixon J, Ansford A et al. Accidental poisoning in childhood: five year urban
population study with 15 year analysis of fatality. British Medical Journal 1984;
288:44–46.
Singhi SC, Baranwal AK, Jayashree M. Acute iron poisoning: clinical picture, intensive
care needs and outcome. Indian Pediatrics 2003: 40(12):1177–1182.
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Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of
Toxicology – Clinical Toxicology 1996; 34(5):485–489.
3.44 ISONIAZID
Isoniazid overdose is rare but potentially fatal. Severe poisoning presents
with rapid onset of seizures, coma and severe metabolic acidosis.
Pyridoxine is the specific antidote.
RISK ASSESSMENT
• Toxicity is of rapid onset, occurring within 30 min to 2 hours
of ingestion and follows a predictable dose–response (see
SPECIFIC TOXINS
Table 3.44.1).
TABLE 3.44.1 Dose-related risk assessment: Isoniazid
Dose Effect
>1.5 g (20 mg/kg) May develop symptoms
>3 g (40 mg/kg) Seizures, metabolic acidosis and coma

273
>10 g (130 mg/kg) Uniformly fatal without intervention
TOXICOLOGY HANDBOOK
Toxic mechanism
Isoniazid is structurally related to pyridoxine, nicotinic acid and NAD. Toxicity results
from a deficiency of the active form of pyridoxine, pyridoxine-5-phosphate (P5P).
Isoniazid interferes with the enzyme responsible for the conversion of pyridoxine to P5P,
pyridoxine phosphokinase, binds to and inactivates P5P and enhances urinary excretion
of P5P. Because P5P is an essential co-factor for the conversion of glutamic acid to
GABA in the CNS, an acute GABA deficiency manifesting as status seizures develops.
The severe lactic acidosis is due to the status seizures and direct inhibition of conversion
of lactate to pyruvate.
Toxicokinetics
Absorption following oral administration is rapid and complete. Peak serum levels occur
within 1–2 hours. Volume of distribution is 0.6 L/kg. Isoniazid undergoes hepatic
metabolism by either acetylation to form acetyl-isoniazid, or hydrolysis by cytochrome
P450 to form hydrazine derivatives. Some drug is excreted unchanged in the urine. There
are ‘fast’ and ‘slow’ acetylators such that the elimination half-life varies from 1 to 4 hours.
CLINICAL FEATURES
• Initial symptoms are light-headedness, blurred vision,
photophobia, nausea and vomiting.
• Physical examination may reveal tachycardia, dilated pupils,
slurred speech, ataxia and hyperreflexia.
• If a sufficient dose is ingested, patients rapidly develop confusion,
depressed level of consciousness, coma, status seizures, severe
lactic acidosis and death.
• Seizures are typically generalised tonic–clonic. They may resolve
spontaneously but then recur promptly. Complications of
prolonged status seizures, including hyperpyrexia, pulmonary
aspiration and rhabdomyolysis, may be observed.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• Arterial blood gas
— Severe anion gap metabolic acidosis with a high serum
lactate is a major feature of isoniazid overdose. The pH may
range from 6.8 to 7.3.
• Isoniazid levels
— Not routinely available, difficult to interpret and do not aid in
acute management. They may be useful to confirm the
diagnosis retrospectively.
SPECIFIC TOXINS
MANAGEMENT
• Isoniazid overdose is a medical emergency and managed in
an area equipped for cardiorespiratory monitoring and
resuscitation.
• Aggressive supportive care of airway, breathing and circulation is
paramount until seizures are controlled and adequate doses of
pyridoxine administered.
274
• The patient presenting unconscious or with seizures undergoes
27
prompt rapid-sequence intubation and ventilation.

4
• Seizures are controlled with high-dose intravenous diazepam

TOXICOLOGY HANDBOOK
while supplies of pyridoxine are secured and administered.

• EEG monitoring if available is useful in the intubated patient.
Decontamination
• Activated charcoal is only given once the airway is secured with
endotracheal intubation and never takes precedence over
resuscitation and supportive care.
• Haemodialysis effectively removes isoniazid, but the time course
of the poisoning is such that this intervention is not clinically
useful.
Antidotes
• Urgent administration of IV pyridoxine is indicated if coma or
seizures develop (see Chapter 4.24: Pyridoxine).
• Give 1 g for each gram of isoniazid ingested.
• If the ingested dose is unknown, give 5 g of pyridoxine and
review response.

• Asymptomatic patients can be observed for 6 hours and
discharged if no symptoms develop and no treatment is
given.
• All patients who develop neurological toxicity should be admitted
to an intensive care or high-dependency unit.
• Any patient who develops seizures is intubated and managed in
intensive care.
ERRNVPHGLFRVRUJ
HANDY TIPS
• Always consider isoniazid overdose in the differential diagnosis of
status epilepticus, particularly if the patient or a household
member has a history of tuberculosis.
• Rapidly ascertain location of all available pyridoxine when
confronted with a possible isoniazid overdose.
• Good resuscitation and use of benzodiazepines can assure a
good outcome even in the absence of pyridoxine.
PITFALL
• Inability to secure adequate doses of IV pyridoxine.
SPECIFIC TOXINS
CONTROVERSIES
• Value of prophylactic administration of pyridoxine to patients with
a history of ingestion of >1.5 g of isoniazid.
• Hospital stocking levels of pyridoxine. At least 5 g is required to
treat one isoniazid overdose.
Presentations
Isoniazid 25 mg tablets (100)
Isoniazid 100 mg tablets (100)
275
Reference
Maw G, Aitken P. Isoniazid overdose: a case series, literature review and survey of
antidote availability. Clinical Drug Investigation 2003; 23:479–485.
TOXICOLOGY HANDBOOK
3.45 LEAD
Acute lead intoxication is usually due to ingestion. It is rare, but
potentially life threatening. Chronic environmental lead exposure remains
a major public health issue in some regions and occupations. Evaluation
of patients with possible lead exposure requires a detailed risk
assessment.
RISK ASSESSMENT
• Acute or subacute severe lead intoxication occurs in the
context of ingestion or inhalational occupational exposure to
lead. It is associated with encephalopathy, cerebral oedema
and death.
• Chronic occupational or environmental exposure usually leads to
a vague multi-system disorder with the potential for permanent
neurological and neuropsychological sequelae.
• Risk of long-term neurological sequelae loosely correlates to
blood lead level (see Table 3.45.1).
• Pregnancy: major malformations are reported in children born to
mothers with elevated lead levels.
• Children: childhood exposure to lead is neurotoxic and
associated with impaired intellectual development. There appears
to be no threshold below which lead is not deleterious during
early childhood development.
ERRNVPHGLFRVRUJ
TABLE 3.45.1 Blood lead level and clinical effects
Blood lead level Effects
<10 microgram/dL Minor dose-dependent reduction in IQ in

(0.48 micromol/L) young children as lead levels increase
towards 10 microgram/dL
>10 microgram/dL Subtle developmental, learning, motor and

(0.48 micromol/L) intellectual abnormalities in children
>30 microgram/dL Non-specific constitutional symptoms such

(1.4 micromol/L) as abdominal pain, malaise, headaches,
hypertension and insomnia
SPECIFIC TOXINS
Subclinical impairment of peripheral nerve

conduction and psychometric testing
may occur
Clinically overt peripheral neuropathies
involving ulnar and radial nerves (wrist
drop) are classical but rare
Renal injury in the form of a chronic
interstitial nephritis or Fanconi’s
276 syndrome may occur
Decreased fertility reported in both sexes
27
6
>100 microgram/dL Severe gastrointestinal symptoms,

TOXICOLOGY HANDBOOK
(4.8 micromol/L) encephalopathy, seizures and coma
Toxic mechanism
Lead has no physiological function. It has toxic effects through interference with
intracellular functions, including maintenance of cell wall integrity, haem synthesis,
neurotransmitter systems and steroid production. Major target organs affected by
lead are the nervous system, kidneys and the reproductive and haematopoietic
systems.
Toxicokinetics
Absorption is via oral, topical and inhaled routes. Absorption from lead foreign bodies
such as shotgun pellets lodged in joints or other body cavities also occurs. Oral
absorption is greater in children than adults (bioavailability 50% and 20%, respectively).
Lead bioavailability is increased with high-fat, low-calcium diets. Fumes from lead
smelting, or inhaled lead dust, are rapidly absorbed by the lungs. Dermal absorption of
organic lead compounds through intact skin can occur. Lead is absorbed and bound by
red cells, then distributed widely throughout the body. The bony skeleton acts as a major
lead store. Other sites of deposition are the CNS, kidneys and spleen. Bone stores can
re-mobilise decades after exposure has ceased, resulting in persistently high levels for
months to years. Lead easily crosses the placenta and significant fetal transfer can
occur. Urinary excretion is the predominant elimination pathway.
CLINICAL FEATURES
• Acute
— Acute ingestion of lead leads to abdominal pain, nausea,
vomiting, haemolytic anaemia and hepatitis.
— Cerebral oedema, encephalopathy, seizures and coma are
pre-terminal conditions.
ERRNVPHGLFRVRUJ
— Clinical effects generally correlate with levels although there is
wide interindividual variation (see Table 3.45.1).
• Chronic
— Vague constitutional symptoms and multi-system effects
include impaired concentration, anorexia, vague abdominal
pain, emotional lability, weight loss, arthralgia and impaired
coordination.
— Subclinical impairment of higher centre functions,
including IQ.
INVESTIGATIONS
SPECIFIC TOXINS
• Whole blood lead level
— Most useful indicator of lead exposure.
• FBC
— Normochromic, normocytic anaemia with basophilic stippling
of erythrocytes is classical but rarely seen.
• EUC, LFTs
• Free erythrocyte protoporphyrin (FEP)
— FEP is a surrogate measure of total body burden of lead, 277
but has low sensitivity at levels below 25 microgram/dL
(1.2 micromol/L).
— FEP is elevated in chronic lead intoxication due to the
TOXICOLOGY HANDBOOK
inhibition of haemoglobin synthesis.
• Abdominal X-ray
— Assists identification of ingested lead foreign bodies.
• Nerve conduction and psychomotor testing
— May be useful in chronic exposures to demonstrate objective
evidence of lead neurotoxicity.
MANAGEMENT
• Acute resuscitation is rarely required.
• In cases of acute lead-induced encephalopathy, management of
airway, breathing and circulation are managed along conventional
lines, as outlined in Chapter 1.2: Resuscitation.
• Administer mannitol 1 g/kg and dexamethasone 10 mg
(1.5 mg/kg in children) if cerebral oedema is present.
• Seizures are treated with benzodiazepines, as outlined in
Decontamination
• Lead foreign body ingestion
— Endoscopic retrieval if located above the gastro-oesophageal
junction.
— If beyond the gastro-oesophageal junction and the patient
is asymptomatic, commence a high-residue diet plus oral
polyethylene glycol to drink at home. Repeat abdominal
ERRNVPHGLFRVRUJ
X-rays every 24 hours to confirm passage of the foreign
body within 72 hours.
— If the foreign body is still present at 72 hours, admit the
patient for formal whole bowel irrigation with polyethylene
glycol (see Chapter 1.6: Gastrointestinal decontamination).
• Shrapnel or bullets adjacent to synovial tissue
— Surgical excision if feasible is indicated in the patient with
symptoms or rising lead levels.
Antidotes
• Chelation therapy is indicated in symptomatic lead poisoning or if
SPECIFIC TOXINS
long-term neurological injury is anticipated.

• Sodium calcium edetate (EDTA), an intravenous chelator, is
indicated for acute lead-induced encephalopathy or the
symptomatic patient with blood level >100 microgram/dL (4.8
micromol/L). For administration see Chapter 4.25: Sodium
calcium edetate.
• Succimer (DMSA), an oral chelator, is used in symptomatic
patients without encephalopathy and asymptomatic patients with
blood lead levels >60 microgram/dL (2.9 micromol/L) for adults or
278 >45 microgram/dL (2.17 micromol/L) for children. For
27
administration see Chapter 4.27: Succimer.

8
TOXICOLOGY HANDBOOK
HANDY TIPS
• Diagnosis of chronic lead intoxication identifies an index case.
Other family members or colleagues should be screened and all
potential exposures considered.
• Lead levels <25 microgram/dL (1.2 micromol/L) are usually
asymptomatic. However, any level >10 microgram/L (0.48
micromol/L) mandates strenuous efforts to identify the source and
prevent further exposure, especially in children.
• Lead intoxication is a notifiable disease in most jurisdictions.
PITFALLS
• Using dicobalt edetate (antidote for cyanide) instead of sodium
calcium edetate (EDTA).
• Failure to identify source of lead exposure in chronic poisoning,
and prevent further exposure.
CONTROVERSIES
• Thresholds for chelation in pregnant women, children and
asymptomatic adults remain controversial and are constantly
under review.
• Value of chelation therapy for children with mild-to-moderate
elevated lead levels (<45 microgram/dL or 2.17 micromol/L). This
intervention does not appear to lead to improved
neuropsychological outcomes.
Sources
Smelting and metal recycling
Atmospheric lead due to leaded petrol
ERRNVPHGLFRVRUJ
Occupations and hobbies (e.g. soldering metal, lead galvanising and painting, jewellery,
stained glass, radiator repairs, battery recycling, plumbing, injection moulding of
plastics, sports shooting)
Lead paint used in housing prior to 1960s (tastes sweet and attractive to children)
Soil contamination – often idiopathic
Fishing sinkers
Antique toys painted with lead paint
Pottery glazes
Lead powder medications available in many developing countries
Make-up (especially from the Indian sub-continent)
Retained bullets near synovial joints
References
Canfield RL, Henderson CR, Cory-Slechta DA et al. Intellectual impairment in children
with blood lead concentrations below 10 microg per deciliter. New England Journal
SPECIFIC TOXINS
of Medicine 2003; 348(16):1517–1526.
Dietrick KN, Ware JH, Salganik M et al. Effect of chelation therapy on neuropsychological
and behavioural development of lead-exposed children after school entry. Pediatrics
2004; 114:19–26.
Keogh JP, Boyer LV. Lead. In: Sullivan JB, Krieger GR, eds. Clinical Environmental
Health and Toxic Exposures. 2nd edn. Philadelphia: Lippincott Williams & Wilkins;
2001:879–889.
Toxicological profile for Lead, ATSDR (Agency for Toxic Substances and Disease
Registry). Available at: http://www.atsdr.cdc.gov/toxprofiles/tp13.pdf [accessed 30
May 2014].
279
3.46 LITHIUM: ACUTE OVERDOSE
TOXICOLOGY HANDBOOK
See also Chapter 3.47: Lithium: Chronic poisoning.
Acute lithium overdose frequently produces acute gastrointestinal
symptoms, including nausea, vomiting, abdominal pain and diarrhoea.
Provided adequate urinary lithium excretion is maintained, significant
neurotoxicity of the type observed with chronic lithium intoxication rarely
develops.
RISK ASSESSMENT
• In the setting of normal renal function, acute ingestion of <25 g is
benign, causing no more than minor gastrointestinal (GI) symptoms.
• Acute ingestion of >25 g may cause more significant GI
symptoms but rarely leads to significant neurotoxicity, provided
that good supportive care is instituted so as to avoid dehydration,
sodium depletion or renal impairment.
• Acute or chronic impairment of renal function, dehydration or
sodium depletion significantly impairs urinary lithium excretion.
Under these conditions, lithium absorbed following acute
overdose is preferentially redistributed to tissue compartments,
including the CNS, rather than excreted, thus enhancing the
potential for progressive onset of neurotoxicity.
• Patients who present late with established neurotoxicity have a
risk assessment similar to that of chronic lithium toxicity (see
Chapter 3.47: Lithium: Chronic poisoning).
• Children: minor paediatric ingestions do not cause toxicity and
do not require hospital assessment unless symptoms develop.
ERRNVPHGLFRVRUJ
Toxic mechanism
Lithium is a monovalent cation primarily used in the management of bipolar disorder.
Like most metal salts, lithium carbonate acts as a direct irritant to the GI tract. Once
absorbed, lithium ions substitute for sodium and potassium ions and are thought to
modulate intracellular second messengers. They may also affect neurotransmitter
(including serotonin) production and release.
Toxicokinetics
Standard-release lithium carbonate preparations are normally completely absorbed within
6 hours of ingestion and peak serum lithium levels occur within 4 hours. Absorption may
be prolonged following overdose, with peak levels delayed up to 12 hours with
slow-release preparations. Lithium is slowly redistributed from the intravascular
compartment to tissue compartments, including the CNS, with a steady-state volume of
distribution of 0.7–0.9 L/kg. Elimination is almost entirely by the kidney. Clearance is
dependent on glomerular filtration and reduced in water- or sodium-depleted states.
SPECIFIC TOXINS
Elimination half-life is 24 hours at steady state.
CLINICAL FEATURES
• Small acute overdoses are often asymptomatic.
• Following larger ingestions, symptoms of acute gastroenteritis
occur early and include nausea, vomiting, abdominal pain and
diarrhoea.
• Significant fluid losses may occur.
280 • Neurological symptoms, if they develop, are delayed, reflecting
slow redistribution into the CNS. The earliest and most frequent
28
0
neurological sign is tremor. Neurotoxic symptoms rarely

progress beyond tremor provided adequate lithium excretion
TOXICOLOGY HANDBOOK
is maintained.
• Patients occasionally present late with established neurotoxicity
(see Chapter 3.47 Lithium: Chronic poisoning for description).
• Minor ST-T wave changes may be observed on the 12-lead ECG.
INVESTIGATIONS
Specific investigations as indicated:
• EUC
— Detect and monitor hyponatraemia.
— Detect and monitor renal impairment.
• Serum lithium levels
— Useful to confirm ingestion and, following larger overdoses,
monitor progress and determine safety of medical discharge.
— Peak levels >5 mmol/L occurring at 4–8 hours post ingestion
are not unusual following acute overdose.
MANAGEMENT
• The patient who presents late with severe GI symptoms requires
fluid resuscitation. Give normal saline 10–20 mL/kg IV and
reassess.
• Maintain adequate hydration and sodium repletion with
intravenous normal saline as necessary. Urine output is ideally
>1 mL/kg/hour.
ERRNVPHGLFRVRUJ
• Monitor fluid and electrolyte status, renal function, serum lithium
and clinical features of neurotoxicity.
• Continuous cardiac monitoring is not required in the absence of
co-ingestants.
Decontamination
• Activated charcoal does not effectively adsorb lithium and is not
indicated.
• Elimination of lithium can be enhanced with haemodialysis;
however, in the patient with normal renal function whose
hydration and sodium repletion are ensured, this relatively minor
enhancement of elimination is not clinically useful.
• Haemodialysis is reserved for patients with established renal
SPECIFIC TOXINS
failure, particularly those who present late with clinical features of
lithium neurotoxicity.
Antidotes
• None available.
• Patients with no clinical evidence of neurotoxicity and a serum
lithium level <2.5 mmol/L and falling do not require further medical 281
care or monitoring.
HANDY TIPS
TOXICOLOGY HANDBOOK
• Coma in the context of acute deliberate self-poisoning is never
due to lithium. It is always due to a co-ingestant or is of non-
toxicological aetiology.
• Patients on long-term lithium therapy do not have a significantly
increased risk of developing neurotoxicity following acute lithium
overdose. The approach to management does not require
modification.
PITFALL
• Failure to distinguish between acute lithium overdose and chronic
lithium toxicity. These represent distinct clinical entities.
CONTROVERSY
• Whole bowel irrigation has been advocated following overdose of
sustained-release preparations. The value of this intervention is
unproven and provides no theoretical benefit over meticulous
supportive care in patients with normal renal function.
Presentations
Lithium carbonate 250 mg standard-release tablets (200)
Lithium carbonate 450 mg slow-release tablets (100)
References
Jaeger A, Saunder P, Kopferschmidt J et al. When should dialysis be performed in
lithium poisoning? A kinetic study in 14 cases of lithium poisoning. Clinical
Toxicology 1993; 31:429–447.
Waring WS. Management of lithium toxicity. Toxicology Reviews 2006; 25(4):221–230.
ERRNVPHGLFRVRUJ
3.47 LITHIUM: CHRONIC POISONING
See also 3.46: Lithium: Acute overdose.
Lithium neurotoxicity develops in patients on lithium therapy when renal
lithium excretion is impaired for any reason.
RISK ASSESSMENT
• Consider lithium intoxication in any patient on lithium therapy who
presents with neurological signs or symptoms.
• Significant obtundation or seizure activity is an indication of
severe toxicity that carries a risk of permanent neurological
SPECIFIC TOXINS
sequelae.
• Serum lithium concentrations correlate poorly with clinical features
of toxicity.
Toxic mechanism
Lithium ions substitute for sodium and potassium ions and are thought to modulate
intracellular second messengers. They may also affect neurotransmitter (including
serotonin) production and release.
Toxicokinetics
282 Lithium is well absorbed following oral administration with peak serum levels within 4
28
hours of administration of a standard-release preparation. Lithium is slowly redistributed

2
from the intravascular compartment to tissue compartments, including the CNS, with a
steady-state volume of distribution of 0.7–0.9 L/kg. Elimination is almost entirely by the
TOXICOLOGY HANDBOOK
kidney. Clearance is dependent on glomerular filtration and reduced in water- or

sodium-depleted states. Elimination half-life is about 24 hours at steady state under
normal conditions.
CLINICAL FEATURES
• The clinical features are principally neurological. The following
classification by Hansen and Amdisen is widely used:
— Grade 1 (mild)
– Tremor, hyperreflexia, agitation, muscle weakness,
ataxia
— Grade 2 (moderate)
– Stupor, rigidity, hypertonia, hypotension
— Grade 3 (severe)
– Coma, seizures, myoclonus.
• Gastrointestinal symptoms are not prominent with chronic
toxicity.
• Clinical features frequently include those of the underlying
precipitating illness.
• The most common causes of impaired lithium excretion are
impaired renal function, diabetes insipidus, sodium depletion,
dehydration and drug interactions.
• Drugs that may impair lithium excretion include non-steroidal
anti-inflammatory drugs, angiotensin-converting enzyme inhibitors,
thiazide diuretics and topiramate.
• Nephrogenic diabetes insipidus and hypothyroidism are
associated with lithium therapy. They may contribute to the
development of toxicity and complicate the clinical presentation.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• Serum lithium level
— Essential to confirm the diagnosis.
— Serial levels are useful in monitoring the progress of a patient
receiving supportive care or haemodialysis.
• EUC
• Thyroid function tests
MANAGEMENT
• Acute resuscitation is unlikely to be necessary except in cases of
extreme neurotoxicity with coma and seizures.
SPECIFIC TOXINS
• Acute volume resuscitation may be required to adequately restore
and maintain effective renal perfusion.
• Careful attention to correcting any water and sodium deficits
and maintaining renal function is essential to maximise lithium
excretion.
• Lithium and any drugs that may impair lithium excretion are ceased.
• Renal function, urine output, electrolytes and serum lithium levels
are closely monitored.
Decontamination 283
• No role in chronic toxicity.
TOXICOLOGY HANDBOOK
• Haemodialysis enhances the elimination of lithium. It is considered
in the patient with neurological dysfunction and a serum lithium
level >2.5 mmol/L. It is most likely to be useful in the presence of
established renal impairment. Prolonged and repeated
haemodialysis sessions may be necessary to eliminate lithium.
Antidotes
• None available.
• Patients with chronic lithium toxicity always require admission.
Resolution of neurological symptoms may be very slow (weeks)
and sometimes incomplete.
HANDY TIPS
• Consider the diagnosis of chronic lithium toxicity in any individual
on lithium who presents unwell, particularly if there is evidence of
neurological dysfunction.
• The patient’s clinical condition may worsen over the initial stages
of inpatient management.
• Lithium neurotoxicity may persist long after serum lithium returns
to therapeutic range because of slow redistribution and clearance
of lithium from the CNS.
PITFALL
• Failure to check a lithium level in the unwell patient on lithium
therapy.
ERRNVPHGLFRVRUJ
CONTROVERSIES
• The indications for haemodialysis are unproven and have not
been evaluated in clinical trials. Most patients can be managed
without dialysis provided they receive adequate fluid and
electrolyte resuscitation and normal renal function is rapidly
re-established.
• Continuous arterio- or venovenous haemofiltration has been
proposed as an alternative to haemodialysis for enhancement of
lithium elimination. Although lower clearances are achieved with
these methods, they are often easier to institute and may minimise
rapid transcellular fluid and electrolyte shifts. At the moment they
can only be recommended if haemodialysis is not available.
SPECIFIC TOXINS
Presentations
Lithium carbonate 250 mg standard-release tablets (200)
Lithium carbonate 450 mg slow-release tablets (100)
References
Hansen HE, Amdisen A. Lithium intoxication. Quarterly Journal of Medicine 1978;
47:123–144.
Oakley P, Whyte IM, Carter GL. Lithium toxicity: an iatrogenic problem in susceptible
individuals. Australian and New Zealand Journal of Psychiatry 2001; 35:833–840.
284 Waring WS. Management of lithium toxicity. Toxicology Reviews 2006; 25(4):221–230.
28
4
3.48 LOCAL ANAESTHETIC AGENTS

TOXICOLOGY HANDBOOK
Amethocaine, Articaine, Benzocaine, Bupivacaine, Levobupivacaine,

Lignocaine, Mepivacaine, Prilocaine, Ropivacaine
Local anaesthetic (LA) toxicity is nearly always the result of a therapeutic
error. It occurs because of incorrect dose, route of administration or
technique. Care for this potentially life-threatening toxicity is primarily
supportive, although use of intravenous lipid emulsion plays an important
role in management of severe cases.
RISK ASSESSMENT
• Most cases of LA toxicity arise from inadvertent intravascular
administration rather than gross overdose.
• Clinical manifestations correspond to the concentration achieved
in the systemic circulation.
• Onset of clinical manifestations is rapid.
• Maximal recommended doses for agents are listed in Table
3.48.1 but toxicity can occur when lower doses are administered
by direct intravenous or intra-arterial injection. Larger doses can
be safely given when co-administered with adrenaline.
• Methaemoglobinaemia is not dose-related, but is more likely to
complicate administration of benzocaine, lignocaine or prilocaine.
• Children: although paediatric fatalities are reported following
ingestion of lignocaine-containing local and topical anaesthetic
preparations, ingested doses <6 mg/kg are safe. Children are
more likely than adults to develop methaemoglobinaemia after LA
administration, including topical administration.
ERRNVPHGLFRVRUJ
TABLE 3.48.1 Maximal dose of selected local anaesthetic
agents
Local anaesthetic Maximal dose (mg/kg)
Bupivacaine 1–2.5
Lignocaine 4–5
Mepivacaine 4–5
Prilocaine 5–7
Ropivacaine 2.5–3
SPECIFIC TOXINS
Toxic mechanism
The LA agents bind reversibly to sodium channels and act on peripheral nerves to inhibit
the sodium flux necessary to initiate and propagate action potentials. Local anaesthetic
agents, especially benzocaine, lignocaine and prilocaine, may also cause
methaemoglobinaemia.
Toxicokinetics 285
The amide LAs are usually administered topically or by injection into skin and
subcutaneous tissues, intravenous regional injection, epidural and intrathecal routes.
Systemic toxic effects correspond to peak concentrations achieved in the systemic
TOXICOLOGY HANDBOOK
circulation and these are influenced by multiple factors, including total dose, rate of
administration, route and location of administration, presence of tourniquets and local
blood flow. Toxicity is rare following ingestion because of extensive first-pass
metabolism. Some preparations contain adrenaline to cause vasoconstriction and
slow the movement of the LA agent away from the site of administration. The amide
LAs have small volumes of distribution and are eliminated by hepatic metabolism,
with elimination half-lives around 2 hours for most agents, but somewhat longer for
bupivacaine.
CLINICAL FEATURES
• Earliest symptoms of LA toxicity are neurological and include
tinnitus, dizziness, anxiety, confusion and perioral numbness.
• More severe toxicity is characterised by:
— CNS effects – seizures, coma
— Cardiovascular effects – bradycardia, hypotension, atrial
and ventricular dysrhythmias, cardiovascular collapse and
asystole
— Respiratory effects – respiratory depression, apnoea.
• CNS toxicity normally manifests before cardiovascular toxicity,
except following massive intravenous overdose where cardiac
arrest may be the first clinical manifestation of toxicity.
• Bupivacaine is particularly cardiotoxic due to prolonged binding
to myocardial tissue.
• Methaemoglobinaemia is not dose-related. It manifests initially as
blue discolouration of the mucous membranes, but may progress
to CNS and cardiovascular manifestations of cellular hypoxia,
culminating in death as methaemoglobin concentrations rise
above 70%.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• EUC, ABGs, methaemoglobin concentration
• Serial ECGs
— May reveal evidence of Na+ channel blockade (prolongation of
PR and QRS intervals, large terminal R wave in aVR).
MANAGEMENT
in Chapter 1.2: Resuscitation. Immediate intubation and
ventilation is indicated if there is evidence of cardiovascular
SPECIFIC TOXINS
toxicity.
• Ventricular dysrhythmias are treated with sodium bicarbonate
100 mEq (2 mEq/kg in children) IV repeated every 1–2 minutes
until restoration of perfusing rhythm (see Chapter 4.24: Sodium
bicarbonate).
• Seizures are treated with benzodiazepines, as described in
• Hypotension should be treated with administration of intravenous
286 crystalloid 20 mL/kg followed by inotropic support if necessary.
28
Decontamination
6
• Not indicated.
TOXICOLOGY HANDBOOK
Antidotes
• Sodium bicarbonate for ventricular dysrhythmias secondary to Na+
channel blockade as described above.
• Intravenous lipid emulsion is indicated in severe cardiovascular
toxicity or cardiac arrest refractory to standard resuscitation
protocols. For details on administration see Chapter 4.15:
Intravenous lipid emulsion.
• Methylene blue is the specific antidote for methaemoglobinaemia
and is administered to all symptomatic patients. For details on
administration see Chapter 4.16: Methylene blue.

• Children who ingest lignocaine-containing teething gels and
other topical preparations do not require hospital assessment
unless >6 mg/kg may have been ingested or symptoms
develop.
• Local anaesthetic toxicity usually occurs in a hospital or clinic
setting. Once resuscitated, the patient should be managed in a
high-dependency or intensive care setting until toxicity resolves.
HANDY TIP
• The development of any neurological symptoms during or shortly
after administration of a LA prompts close observation in an area
equipped for cardiorespiratory monitoring and resuscitation.
ERRNVPHGLFRVRUJ
CONTROVERSY
• The threshold for trial of intravenous lipid emulsion in the
management of CNS or cardiovascular manifestations of LA
toxicity.
Presentations
Amethocaine HCl 0.5% eye drops Lignocaine 2.5%/prilocaine 2.5% eutectic
Amethocaine HCl 1% eye drops mixture, patches (1 g)
Amethocaine HCl gel 4% (30 g) Lignocaine HCL 5%/chlorhexidine 0.05%
Articaine HCl 40 mg/mL/adrenaline syringe (10 mL)
1 : 100 000 vials (1.7 mL, 2.2 mL) Lignocaine HCL 20 mg/mL/adrenaline
Benzocaine topical oropharyngeal and 12.5 microgram/mL cartridges
otic preparations (2.2 mL)
Bupivacaine HCl 0.125% injectable Lignocaine HCl 3%/cetrimol 0.5% gel
SPECIFIC TOXINS
(100 mL, 200 mL) (25 g)
Bupivacaine HCl 0.25% injectable (20 mL, Lignocaine HCl 2%/cetrimol 0.25% spray
100 mL) (125 mL)
Bupivacaine HCl 0.5% injectable (4 mL, Lignocaine HCl 1%/cetrimol 1%/
10 mL, 20 mL) chlorhexidine 0.2% cream (50 g)
Bupivacaine HCl 0.125%/fentanyl citrate 5 Lignocaine HCl 2%/adrenaline 1 : 80,000
microgram/mL injectable (20 mL, injectable (5 mL)
200 mL) Lignocaine HCl 1%/adrenaline 1 : 100,000
Bupivacaine HCl 0.25%/adrenaline injectable (5 mL)
1 : 400 000, injectable (20 mL) Lignocaine HCl 2%/adrenaline 1 : 200,000 287
Bupivacaine HCl 0.5%/adrenaline injectable (20 mL)
1 : 200 000, injectable (20 mL) Lignocaine HCl 1%/adrenaline 1 : 200,000
Bupivacaine HCl 0.5%/glucose 80 mg/mL injectable (20 mL)
TOXICOLOGY HANDBOOK
injectable (4 mL) Mepivacaine 2% cartridges (2.2 mL)
Levobupivacaine 0.0625% injectable Mepivacaine 3%/adrenaline 1 : 100,000
(200 mL) cartridges (1.8 mL, 2.2 mL)
Levobupivacaine 0.125% injectable Prilocaine HCl 0.5% injectable (50 mL)
(200 mL) Prilocaine HCl 1% injectable (5 mL)
Levobupivacaine 0.25% injectable (10 mL) Prilocaine HCl 2% injectable (2 mL, 5 mL)
Levobupivacaine 0.5% injectable (10 mL) Prilocaine HCl 4% cartridges (2.2 mL)
Levobupivacaine 0.75% injectable (10 mL) Prilocaine HCl 3%/adrenaline 1 : 300 000
Lignocaine HCl 2% oral liquid (200 mL) cartridges (2.2 mL)
Lignocaine HCl 0.5% injectable (5 mL) Prilocaine HCl 3%/felypressin 0.03 IU/mL
Lignocaine HCl 1% injectable (2 mL, cartridges (2.2 mL)
5 mL, 20 mL) Ropivacaine HCl 2 mg/mL injectable
Lignocaine HCl 2% injectable (5 mL, (10 mL, 20 mL, 100 mL, 200 mL)
20 mL) Ropivacaine HCl 5 mg/mL injectable
Lignocaine HCl 2% gel (10 g, 20 g, 30 g) (10 mL)
Lignocaine HCl 4% cream (5 g, 30 g) Ropivacaine HCl 7.5 mg/mL injectable
Lignocaine HCl 4% topical solution (10 mL, 20 mL, 100 mL, 200 mL)
(30 mL) Ropivacaine HCl 10 mg/mL injectable
Lignocaine HCL 5% ointment (15 g) (10 mL, 20 mL)
Lignocaine HCl 10% pump spray (50 mL) Ropivacaine HCl 2 mg/mL/fentanyl 2
Lignocaine HCL 5% patch (30) microgram/mL injectable (100 mL,
Lignocaine HCL 5%/phenylephrine HCl 200 mL)
0.5% nasal spray (15 mL, 50 mL) Ropivacaine HCl 2 mg/mL/fentanyl 4
Lignocaine 2.5%/prilocaine 2.5% eutectic microgram/mL injectable (100 mL,
mixture, cream (5 g, 30 g) 200 mL)
References
Balit CR, Lynch AM, Gilmore SP et al. Lignocaine and chlorhexidine toxicity in children
resulting from mouthpaint ingestion: a bottling problem. Journal of Paediatrics and
Child Health 2006; 42(6):350–353.
ERRNVPHGLFRVRUJ
Curtis LA, Dolan TS, Seibert HE. Are one or two dangerous? Lidocaine and topical
anesthetics exposure in children. Journal of Emergency Medicine 2009; 37:32–39.
Felice KL, Schumann HM. Intravenous lipid emulsion for local anesthetic toxicity: a
review of the literature. Journal of Medical Toxicology 2008; 4(3):184–191.
Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity.
Toxicological Reviews 2006; 25(3):139–145.
3.49 MERCURY
Elemental mercury, Inorganic mercury, Organic mercury, Merbromin
Mercury intoxication is now rare. Most exposures come from
consumption of seafood. Accidental ingestion of elemental thermometer
SPECIFIC TOXINS
mercury or amalgam mercury present minimal risk. Occupational

exposures and deliberate self-poisoning with mercury may cause serious
morbidity or mortality.
RISK ASSESSMENT
• Benign presentations
— Accidental ingestion of elemental mercury (e.g. from a broken
thermometer) in a normal intact gastrointestinal tract.
— Incidental discovery of elevated mercury levels in an
288 asymptomatic patient undergoing a ‘heavy metal screen’.
28
— Concern about dental amalgams.

8
• Potentially serious presentations

— Inhalation of mercury aerosol (after vacuuming or prolonged
TOXICOLOGY HANDBOOK
stasis) or vapour (heating of elemental mercury). Pneumonitis,

acute non-cardiac pulmonary oedema and neurological injury
may occur.
— Ingestion of inorganic mercury salts, leading to haemorrhagic
gastroenteritis, acute renal failure and shock. Potential lethal
dose is 30–50 mg/kg.
— Exposure to organic mercury compounds by ingestion,
inhalation or dermal application, leading to neurological injury.
• Undefined risk
— Injection of elemental mercury SC or IV, leading to mercuric
pulmonary emboli. This creates depots from which distribution
of mercury to the brain may occur over the long term.
— Intentional ingestion of merbromin (Mercurochrome) is
associated with high mercury levels, although long-term
sequelae are not reported.
• Children: minor unintentional ingestion or skin exposure to
elemental mercury or Mercurochrome antiseptic solution does not
warrant medical assessment, observation or investigation.
Toxic mechanism
Mercury is a metal with no natural cellular function. It binds to sulfhydryl (SH–) groups at
multiple intracellular sites, causing inhibition of enzymes and disruption of cellular
membranes.
Toxicokinetics
There is minimal absorption of elemental mercury from an intact gastrointestinal (GI)
tract. In contrast, elemental mercury is well absorbed from the respiratory tract when
inhaled as either an aerosol (produced when it is vacuumed) or vapour (produced when it
ERRNVPHGLFRVRUJ
is heated). About 10% of a dose of inorganic mercury is absorbed following ingestion.
Inorganic mercury is also significantly absorbed when applied to skin or mucous
membranes. Organic mercury is readily absorbed from both the GI tract and via
inhalation. Absorption also occurs across disrupted skin. Mercury has a large volume of
distribution and is deposited in the kidneys, liver, spleen and CNS. The high lipid
solubility of elemental and organic mercury compounds favours distribution to the CNS.
Mercuric ions are excreted by the kidney and across the GI tract into faeces. The
elimination half-life of elemental mercury and inorganic mercury is 30–60 days. Organic
mercury is eliminated primarily in the faeces and undergoes enterohepatic circulation.
Half-life is approximately 70 days.
CLINICAL FEATURES
• Acute exposure to elemental mercury – acute intoxication
develops following inhalation of vaporised or aerosolised mercury.
Within a few hours there is the abrupt onset of headache, nausea,
SPECIFIC TOXINS
vomiting, chills, fever, salivation, metallic taste, visual disturbances,
dyspnoea and dry cough. Respiratory failure secondary to
interstitial pneumonitis may occur over the following days.
• Acute exposure to inorganic mercury salts – acute ingestion
causes severe haemorrhagic gastroenteritis within hours. The
patient experiences severe local oropharyngeal pain, a metallic
taste, nausea, vomiting and diarrhoea. Grey discolouration of the
mucous membranes may be noted. Massive fluid loss leading to
hypotension, shock and acute tubular necrosis follows. 289
• Acute exposure to organic mercury – acute manifestations
include GI symptoms, tremor, respiratory distress and dermatitis,
renal tubular dysfunction and ECG (ST segment) changes.
TOXICOLOGY HANDBOOK
Delayed neurotoxicity develops weeks or months after initial
exposure and is usually permanent. It is most severe in children
who have suffered prenatal exposure. Organic mercury is
excreted in breast milk and can produce toxicity in infants.
Delayed neurological sequelae include:
— Psychological – poor concentration, short- and long-term
memory loss, emotional lability, depression and coma
— Cerebellar – ataxia, incoordination and dysdiadochokinesis
— Sensory – glove-stocking paraesthesia of distal limbs, tunnel
vision, deafness, scanning speech with slurring and dysphagia
— Motor – spasticity, tremor, weakness and paralysis.
• Chronic mercury toxicity – chronic exposure to elemental
mercury vapour or inorganic mercury salts leads to the insidious
onset of a multi-system disorder with prominent neuropsychiatric
symptoms:
— Neurological – tremor, neurasthenia (fatigue, depression,
headaches, hypersensitivity, lack of concentration, general
weakness), erethism (blushing and intense shyness),
emotional lability, insomnia, delirium, mixed sensorimotor
neuropathy, ataxia, tunnel vision, anosmia
— Gastrointestinal – metallic taste, burning pain in the mouth,
gingivostomatitis, loose teeth, nausea, hypersalivation
— Renal dysfunction – Proximal tubular atrophy with mercuric
deposits within the renal interstitium and macrophages
— Acrodynia (usually children) – erythematous, oedematous,
hyperkeratotic indurated rash of the palms, soles and face. It
often progresses to desquamation and ulceration.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• Whole blood mercury level (normal: <20 microgram/L (100 nmol/L))
— Level >200 microgram/L (1000 nmol/L) is associated with
symptoms.
— Level may be >500 microgram/L (2500 nmol/L) following acute
inorganic mercury exposure.
— Confirms recent exposure but does not reflect total body
burden.
• 24 hour urine mercury level (normal: <10 microgram/L (50 nmol/L)
SPECIFIC TOXINS
— Level >100 microgram/L (500 nmol/L) is associated with

neuropsychiatric disturbance.
• X-rays
— Elemental mercury is radio-opaque and X-rays confirm
ingestion, subcutaneous or intravenous injection.
— Intravenous injection produces multiple mercuric pulmonary
emboli and a characteristic ‘milky way’ appearance on chest
X-ray.
• Endoscopy
290 — May be indicated to assess corrosive GI injury.
29
0
MANAGEMENT
TOXICOLOGY HANDBOOK
• Accidental oral or skin exposure to elemental mercury does not

require medical assessment or management.
• Following other acute exposure, attention to airway, breathing and
circulation are paramount. These priorities are managed along
conventional lines, as outlined in Chapter 1.2: Resuscitation.
• Inhalational exposure to mercury vapour requires close clinical
and physiological monitoring and general supportive care
measures, as outlined in Chapter 1.4: Supportive care and
monitoring.
• Ingestion of inorganic mercury requires aggressive fluid
resuscitation and general supportive care measures for multiple
organ failure.
• Exposure to organic mercury requires general supportive care
measures, as outlined in Chapter 1.4: Supportive care and
monitoring.
Decontamination
• Decontamination is aimed at preventing further exposure to
mercury.
— Environmental
– Seek advice regarding mercury spills.
– Avoid vacuuming.
– Discard contaminated carpets or surfaces.
— Individual
– Elemental mercury.
Remove contaminated clothing.
Remove mercury from skin.
ERRNVPHGLFRVRUJ
Administration of oral polyethylene glycol solution
enhances removal from the GI tract following
deliberate ingestion of massive volumes.
Surgical excision of subcutaneous mercury depots or
residues following SC injection should be
undertaken where feasible.
– Organic mercury compounds.
Administer activated charcoal.
• Not clinically useful for elemental or inorganic mercury toxicity.
• Administration of polythiol resin may interrupt enterohepatic
circulation of organic mercury compounds.
SPECIFIC TOXINS
Antidotes
• Chelation therapy with dimercaprol, penicillamine or succimer (see
Chapter 4.7: Dimercaprol, Chapter 4.20: Penicillamine and
Chapter 4.27: Succimer).
— Chelation therapy is indicated when there are objective clinical
features of mercury intoxication or if markedly elevated urine
or blood mercury levels indicate potential for significant
morbidity.
— Chelation is only useful once further exposure to mercury is
terminated by decontamination of the environment or 291
individual.
— Note: Dimercaprol is only used for inorganic mercury salt
TOXICOLOGY HANDBOOK
exposure.

• Patients exposed to mercury vapour or aerosol are counselled
regarding appropriate measures to cease exposure and clean up
remnant environmental contamination.
• Symptomatic patients require admission for further management.
• Patients with potential ingestion of inorganic or organic mercury
require admission for observation and aggressive management
should clinical features develop.
HANDY TIP
• Dimercaprol is contraindicated following elemental or organic
mercury exposure, as there is concern that it increases
distribution of mercury to the brain.
PITFALL
• Ordering ‘heavy metal screens’ on patients with non-specific
symptoms without exposure assessment – these are rarely
clinically useful.
CONTROVERSIES
• The indications for chelation therapy. Dimercaprol does not reduce
symptoms of organic mercury intoxication. Succimer reduces
mercury levels but has not been shown to alter prognosis.
• Value of long-term chelation therapy following IV or SC injection
of mercury if decontamination cannot be adequately achieved.
ERRNVPHGLFRVRUJ
• The literature does not support the routine replacement of
mercury dental amalgams.
Sources
Elemental mercury (Hg0): dental amalgam, thermometers, barometers, manufacture of
chlorine and caustic soda, paints, pigments and gold mining
Inorganic mercury (mercuric acetate, mercuric arsenate, mercuric bromide,
mercuric chloride, mercuric potassium cyanide, mercuric sulfide): disinfectants,
fireworks and explosives, processing of fur and leather, waterproofing and
antifouling paints, photographic plates, batteries
Organic mercury (alkoxyalkyl mercury, alkyl mercury, methyl mercury): embalming
fluid, fungicides, pesticides, wood preservatives, seafood
Merbromin
SPECIFIC TOXINS
References
Brownawall AM, Berent S, Brent RL et al. The potential adverse effects of dental
amalgam. Toxicological Reviews 2005; 24(1):1–10.
Clarkson TW, Magos L, Myers GJ. The toxicology of mercury: current exposures and
clinical manifestations. New England Journal of Medicine 2003; 349:1731–1737.
Kales SN, Goldman RH. Mercury exposure: current concepts, controversies, and a
clinic’s experience. Journal of Occupational and Environmental Medicine 2002;
44:143–154.
292
3.50 METFORMIN
29
2
Metformin can produce life-threatening lactic acidosis. This may occur in

TOXICOLOGY HANDBOOK
patients on therapeutic doses who develop renal failure or, less

commonly, following large acute ingestions. Early recognition and
haemodialysis are life saving.
RISK ASSESSMENT
• Lactic acidosis in a patient on therapeutic metformin usually
occurs in the context of acute renal failure or severe sepsis and is
associated with a mortality exceeding 50%.
• Metformin overdose is usually benign, but severe lactic acidosis is
reported. The threshold dose of concern remains undefined but is
thought to be >10 g.
• Lactic acidosis is more likely to develop following acute overdose
if there is pre-existing impairment of renal function or if
cardiovascular toxicity of co-ingestants results in impaired renal
perfusion.
• The prognosis for severe lactic acidosis from metformin overdose
remains good provided there is early recognition and institution of
haemodialysis.
• Children: unintentional ingestion of up to 1700 mg is benign and
does not require hospital assessment.
Toxic mechanism
Metformin inhibits gluconeogenesis, reduces hepatic glucose output and stimulates
peripheral glucose uptake. The chief agent of toxicity is lactate. Metformin can
produce a type B (non-aerobic) lactic acidosis, possibly by changing the intracellular
redox potential and increasing cellular production, and by inhibiting hepatic uptake of
lactate.
ERRNVPHGLFRVRUJ
Toxicokinetics
Metformin is rapidly and well absorbed following oral administration, with peak levels
occurring at 2 hours. It is not metabolised and elimination is entirely dependent on renal
excretion.
CLINICAL FEATURES
• Acute metformin overdose is usually asymptomatic.
• Lactic acidosis, if it develops, manifests some hours following the
overdose, with worsening non-specific features including altered
sensorium, nausea, vomiting, diarrhoea, dyspnoea, tachycardia,
hypotension and cool peripheries.
• Lactic acidosis may progress to coma, shock and death.
• Hypoglycaemia, if it develops at all, is usually minor and easily
corrected by dextrose administration.
SPECIFIC TOXINS
• Patients who develop lactic acidosis on therapeutic metformin
present unwell with a history of progressively worsening clinical
features as described above. There is nearly always coexisting
acute renal failure and/or sepsis.
INVESTIGATIONS
293
• Electrolytes, renal function tests, arterial blood gases, serum
lactate
TOXICOLOGY HANDBOOK
— Confirm diagnosis of lactic acidosis.
— Indicated in any unwell patient on metformin and any patient
with clinical deterioration following metformin overdose.
MANAGEMENT
• General supportive care measures, as outlined in Chapter 1.4:
Supportive care and monitoring ensure a good outcome in the
• Administration of sodium bicarbonate to control severe acidosis
(see Chapter 4.24: Sodium bicarbonate) and control of
hyperkalaemia help stabilise the severely unwell patient while
awaiting haemodialysis.
Decontamination
• Administer oral activated charcoal to the co-operative patient who
presents within 2 hours of deliberately self-poisoning with >10 g
of metformin.
• Haemodialysis not only rapidly corrects acidosis, but also
removes metformin, thus preventing further lactate production. It
is urgently indicated in:
— Any unwell patient with lactic acidosis from therapeutic
administration
ERRNVPHGLFRVRUJ
— Worsening lactic acidosis following acute overdose where
signs of clinical instability are present or emerging.
• Haemodialysis may need to be prolonged >15 hours.
Antidotes
• None available.
• Children who acutely ingest up to 1700 mg of metformin may be
safely observed at home.
• Deliberate self-poisoning with >10 g of metformin mandates
observation for at least 8 hours. Patients who remain well with a
normal bicarbonate at the end of that period may be medically
cleared.
SPECIFIC TOXINS
• Patients who present with or develop lactic acidosis require

critical care admission, monitoring and assessment for urgent
haemodialysis.
HANDY TIP
• Consider the diagnosis of lactic acidosis when confronted with
any unwell patient on metformin or any patient who becomes
unwell following acute self-poisoning with metformin.
294
29
PITFALLS
4
• Treating metformin overdose as a sulfonylurea overdose – they

TOXICOLOGY HANDBOOK
are both antidiabetic medications but belong to different classes

and have different toxicities and risk assessments.
• Failure to consider the diagnosis of metformin-induced lactic
acidosis.
CONTROVERSIES
• Precise indications for initiating haemodialysis in metformin-
associated lactic acidosis following overdose. It is probably safe
to tolerate lactates of up to 10 mmol/L, provided the patient has
normal renal function and a stable cardiovascular system.
• Relative efficacy of various haemodialysis methods. Both
intermittent and continuous haemodialysis techniques have been
used successfully.
Presentations
Metformin hydrochloride 500 mg tablets (100)
Metformin hydrochloride 500 mg controlled release tablets (120)
Metformin hydrochloride 1000 mg controlled release tablets (60)
Metformin hydrochloride 250 mg/glibenclamide 1.25 mg tablets (90)
Metformin hydrochloride 500 mg/glibenclamide 2.5 mg tablets (90)
Metformin hydrochloride 250 mg/glibenclamide 5 mg tablets (90)
References
Guo PYF, Storsley LJ, Finkle SN. Severe lactic acidosis treated with prolonged
haemodialysis: recovery after massive overdose of metformin. Seminars in Dialysis
2006; 19(1):80–83.
ERRNVPHGLFRVRUJ
Seidowsky A, Nseir S, Houdret N et al. Metformin-associated lactic acidosis: a
prognostic and therapeutic study. Critical Care Medicine 2009; 37(7):2191–2196.
Spiller HA, Weber JA, Winter ML et al. Multicenter case series of pediatric metformin
ingestion. Annals of Pharmacotherapy 2000; 34:1385–1388.
Teale KFH, Devine A, Stewart H et al. The management of metformin overdose.
Anaesthesia 1998; 53:698–701.
3.51 METHOTREXATE
The toxic effects of this antimetabolite are employed therapeutically in
the treatment of a variety of neoplastic conditions, psoriasis and
rheumatoid arthritis. Toxicity is not described following acute overdose,
but severe toxicity occurs following repeated supratherapeutic dosing.
SPECIFIC TOXINS
Folinic acid is used as an antidote in selected cases.
RISK ASSESSMENT
• Acute overdose
— Toxicity is not described following acute deliberate self-
poisoning (single ingestion).
— Methotrexate levels taken following acute overdose suggest
that toxic levels are not attained where less than 500 mg
is ingested (5 mg/kg in children) (see Table 3.51.1 and 295
Table 3.51.2).
TOXICOLOGY HANDBOOK
TABLE 3.51.1 Dose-related risk assessment: Acute
methotrexate overdose
Dose Toxicity
Single dose <500 mg (<5 mg/kg in children) Toxic levels unlikely
Single dose >500 mg (>5 mg/kg in children) Toxic levels possible
TABLE 3.51.2 Threshold blood levels for toxicity following a

single acute overdose of methotrexate
Time since ingestion (h) Methotrexate level (micromol/L)
6 5
12 1
24 0.1
• Repeated supratherapeutic ingestion

— Associated with potentially lethal bone marrow suppression.
— Toxicity may develop if the weekly therapeutic oral dose is
taken on as few as 3 consecutive days.
— Patients with renal impairment and the malnourished are
more susceptible to methotrexate-induced bone marrow
suppression.
ERRNVPHGLFRVRUJ
• Intrathecal overdose
— Potentially lethal.
• Children: toxicity is not reported after acute ingestion, but single
ingestion suspected to be >2.5 mg/kg warrants referral to hospital
for assessment including a methotrexate level.
Toxic mechanism
Methotrexate is a structural analogue of folate. It acts by competitive inhibition of
dihydrofolate reductase and thymidylate synthetase, resulting in decreased DNA and
RNA synthesis, and hence decreased cell replication. Methotrexate toxicity is related to
inhibition of dividing cells (e.g. gastrointestinal tract, bone marrow, hair). Renal and
hepatic injuries are also noted.
Toxicokinetics
SPECIFIC TOXINS
Intestinal absorption of orally administered methotrexate is saturable. Peak levels occur

at 1–2 hours post ingestion. The volume of distribution is 0.4–0.8 L/kg, with 50% protein
binding. Up to 80% is excreted by the kidney unchanged. Hepatic metabolism creates a
nephrotoxic metabolite (7-hydroxymethotrexate), which accumulates at high doses.
Elimination half-life increases with dose, accounting for the accumulation and severe
toxicity seen with inadvertent daily dosing. In supratherapeutic toxicity, intracellular
polyglutamated forms of methotrexate mediate prolonged anti-metabolite effects even
after serum levels have declined.
296 CLINICAL FEATURES

• Most patients remain asymptomatic after acute ingestion.
29
•
6
Following repeated supratherapeutic ingestion, patients

present with clinical features and complications of
TOXICOLOGY HANDBOOK
gastrointestinal, bone marrow, hepatic and renal injury.

Stomatitis is an early sign. Nausea, vomiting and diarrhoea are
common. Pallor and fatigue indicate anaemia, which reaches
a nadir at 7–14 days.
INVESTIGATIONS
• Methotrexate level and renal function
— Following acute single overdose, a timed methotrexate level
and renal function tests determine the need for folinic acid
rescue.
— If folinic acid is indicated, follow-up methotrexate levels
determine the duration of therapy.
• EUC, FBC, liver function tests
MANAGEMENT
In patients presenting with established methotrexate toxicity
managed along conventional lines, as outlined in Chapter 1.2:
Resuscitation.
• Supportive care includes meticulous fluid resuscitation and
management of sepsis.
ERRNVPHGLFRVRUJ
In patients presenting following acute overdose
• Ingestion <500 mg (<5 mg/kg in children).
— Ensure adequate hydration.
— Check renal function and methotrexate level at 6 or more
hours post ingestion.
• Ingestion >500 mg (>5 mg/kg in children).
— Administer activated charcoal.
— Ensure adequate hydration.
— Commence folinic acid.
— Check renal function and methotrexate level at 6 or more
hours post ingestion.
• If renal function is normal and the serum methotrexate level is
below thresholds for toxicity (see Table 3.51.2), further folinic acid
is not indicated and the patient may be medically cleared if
SPECIFIC TOXINS
otherwise well. A follow-up FBC is recommended at 7 days.
• Folinic acid is indicated if a methotrexate level cannot be obtained
within 24 hours, the patient is symptomatic, renal function is
abnormal or the methotrexate level is above the threshold for
toxicity.
Decontamination
• Oral activated charcoal 50 g (1 g/kg in children) is indicated in
cooperative patients who present within 2 hours of acute
overdose of >5 mg/kg. 297
• Not clinically useful in the management of acute oral overdose in
TOXICOLOGY HANDBOOK
patients with normal renal function.
Antidotes
• Folinic acid (Leucovorin) is indicated in patients at potential risk of
methotrexate toxicity (see above). Administer folinic acid 15 mg
PO, IM or IV every 6 hours. For a single acute methotrexate
overdose, therapy may be ceased when the methotrexate level is
confirmed to be below threshold for toxicity (see Table 3.51.2). It
is otherwise continued until the serum methotrexate is <0.05
micromol/L.
• With chronic toxicity, therapy should be continued for at least 3
days, until the serum methotrexate is <0.05 micromol/L and
evidence of bone marrow recovery is documented.
• Refer to Chapter 4.10: Folinic acid for further detail on
administration and therapeutic end points.

• Children who ingest <2.5 mg/kg do not require referral to hospital.
• Most patients with acute oral overdose can be medically cleared
by 24 hours, provided a methotrexate level can be obtained within
that time frame.
• Patients who require folinic acid require close supervision to
complete therapy and for monitoring of blood counts and
methotrexate levels.
• Patients with established methotrexate toxicity are admitted for
supportive care and monitoring and folinic acid therapy.
ERRNVPHGLFRVRUJ
HANDY TIP
• Methotrexate levels are not available in all hospitals. A result can
usually be obtained within 24 hours by sending blood (rather than
the patient) elsewhere.
PITFALLS
• Failure to recognise the potential lethality of repeated
supratherapeutic dosing.
• Administration of folic acid instead of folinic acid as an
antidote.
CONTROVERSIES
• Risk assessment and management plans for acute methotrexate
SPECIFIC TOXINS
overdose have been extrapolated from experience with

therapeutic parenteral dosing. Poor outcomes associated with
acute overdose are not described and methotrexate levels may
not be useful in predicting risk of poor outcome in this setting.
• The management plan outlined is based on consideration of
methotrexate pharmacokinetics and a small prospective case
series published only in abstract form.
• The thresholds for risk of toxicity following repeated
298 supratherapeutic dosing are not well established.
• Granulocyte colony-stimulating factor (GCSF) has been used for
29
8
established bone marrow depression but the efficacy of this

intervention is not established.
TOXICOLOGY HANDBOOK
• Glucarpidase is a recombinant bacterial enzyme that cleaves

methotrexate into inactive metabolites. It has been used as
rescue therapy following high-dose methotrexate used to treat
malignancies in patients with impaired renal function, or following
inadvertent intrathecal administration. It has not been used in
other settings to treat methotrexate toxicity.
Presentations
Methotrexate 2.5 mg tablets (30)
Methotrexate 10 mg tablets (15, 50)
Methotrexate 2.5 mg/mL injectable (2 mL)
Methotrexate 25 mg/mL injectable (2 mL, 20 mL)
Methotrexate 100 mg/mL injectable (10 mL, 50 mL)
References
Bebarta VS, Hensley MD, Borys DJ. Acute methotrexate ingestions in adults: a report of
serious clinical effects and treatments. Journal of Toxicology 2014; 2014:214574.
Lovecchio F, Katz K, Watts D et al. Four-year experience with methotrexate exposures.
Journal of Medical Toxicology 2008; 4(3):149–150.
3.52 MIRTAZAPINE
Deliberate self-poisoning with this novel tetracyclic antidepressant
usually follows a benign course, with mild CNS depression and
tachycardia the most frequently reported clinical features. Care is
supportive.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Mirtazapine overdose is associated with relatively minor clinical
effects, even after large ingestions.
• Children: accidental ingestion of up to 100 mg is not associated
with significant symptoms. Referral to hospital is not required
unless symptoms occur.
Toxic mechanism
Mirtazapine is a centrally acting alpha-2-adrenergic antagonist that enhances release of
serotonin and noradrenaline. It is also acts as an antagonist at serotonin (5-HT2, 5-HT3)
and histamine (H1) receptors.
Toxicokinetics
SPECIFIC TOXINS
Mirtazapine is rapidly absorbed following oral administration. It is 85% protein bound
and has a very large volume of distribution (>100 L/kg). It undergoes hepatic metabolism
by cytochrome P450 (2D6 and 3A4) and metabolites are excreted in the urine. A
significant first-pass effect occurs. Elimination half-life is 20–40 hours.
CLINICAL FEATURES
• Many patients remain asymptomatic. If symptoms occur, onset is
within the first 4 hours.
• Mild tachycardia, hypertension and drowsiness may occur
299
particularly with larger doses.
• CNS depression is more likely with ingestion of >1000 mg but
rarely is it severe enough to warrant endotracheal intubation.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
MANAGEMENT
• Intubation for airway control is rarely necessary.
Decontamination
Antidotes
• None available.
• Patients who are asymptomatic with normal 12-lead ECG
and vital signs at 4 hours post ingestion are fit for medical
discharge.
• Patients with mild sedation are managed supportively in
a ward environment. They are fit for medical discharge
when clinically well, ambulant, passing urine, eating and
drinking.
ERRNVPHGLFRVRUJ
HANDY TIP
• Coma, seizures or significant alteration in vital signs prompts
consideration of alternative diagnoses and revision of the risk
assessment.
Presentations
Mirtazapine 15 mg tablets (30)
Reference
Berling I, Isbister GK. Mirtazapine overdose is unlikely to cause major toxicity. Clinical
Toxicology 2014; 52:20–24.
SPECIFIC TOXINS
3.53 MONOAMINE OXIDASE INHIBITORS (MAOIs)

Irreversible non-selective (MAO-A+B): Phenelzine, Tranylcypromine
Irreversible selective (MAO-B): Selegiline Reversible selective (MAO-A):
Moclobemide
Irreversible non-selective MAO inhibitors are associated with
300 potentially lethal serotonin toxicity in overdose, significant adverse
30
reactions and a withdrawal syndrome. Isolated overdose of the newer

0
reversible and selective agents is associated with a benign clinical

course unless there is co-ingestion of other serotonergic agents. In
TOXICOLOGY HANDBOOK
these cases, the clinical course may be complicated by severe serotonin

syndrome.
RISK ASSESSMENT
• Overdose of moclobemide alone causes minor symptoms only,
irrespective of dose.
— Non-life-threatening serotonin syndrome occurs in <5%.
— QTc prolongation >500 ms may occur with ingestions >3 g
but torsades de pointes is not reported.
• Co-ingestion of moclobemide with other serotonergic agents is
associated with a high risk of severe serotonin syndrome,
irrespective of dose (see Chapter 2.8: Serotonin syndrome).
• Phenelzine and tranylcypromine are associated with dose-
dependent, potentially lethal serotonin and sympathomimetic
toxicity. Symptoms are delayed and prolonged.
— Dose-related risk assessment phenelzine:
– >2 mg/kg associated with toxicity
– 4–6 mg/kg potentially fatal.
— Dose-related risk assessment tranylcypromine:
– >1 mg/kg associated with toxicity
– 170 mg has caused a fatality.
• Children: potential ingestion of 1–2 phenelzine or tranylcypromine
tablets may be associated with toxicity and referral to hospital
for assessment and observation is indicated. Isolated ingestion
of moclobemide is benign and referral to hospital is not
indicated.
ERRNVPHGLFRVRUJ
Toxic mechanism
MAOIs inhibit monoamine oxidase (A and B) in a selective or non-selective, reversible
or irreversible manner. MAO-A metabolises serotonin, noradrenaline and dopamine.
MAO-B metabolises phenylethylamine and benzylamine at central and peripheral
synaptic sites. Irreversible blockade requires new enzyme synthesis over days to
re-establish enzymatic function. Irreversible non-selective agents in overdose lead
to an accumulation of serotonin, adrenaline, noradrenaline, dopamine and
phenylethylamine, resulting in serotonin and sympathomimetic toxicity that can
persist for days.
Toxicokinetics
All MAOIs are well absorbed after oral administration and reach peak levels within 2–3
hours. There is considerable first-pass metabolism (e.g. moclobemide bioavailability
60–80%). They have moderate volumes of distribution (moclobemide 1.2 L/kg). These
agents undergo hepatic metabolism to metabolites that are excreted in the urine.
SPECIFIC TOXINS
Phenelzine, tranylcypromine and selegiline have active metabolites.
CLINICAL FEATURES
• Moclobemide overdose (no co-ingestions)
— Minor symptoms only.
— Nausea, anxiety and tachycardia may occur.
— Serotonin syndrome is rare.
• Moclobemide overdose in combination with another serotonergic
agent 301
— Serotonin syndrome frequently develops within 6–12 hours
(see Chapter 2.8: Serotonin syndrome).
• Phenelzine or tranylcypromine overdose
TOXICOLOGY HANDBOOK
— Patients are usually asymptomatic for the first
6–12 hours.
— Onset of toxicity is heralded by restlessness, agitation,
tachycardia, involuntary movements, grimacing, clonus and
hyperreflexia.
— A rapid decline in conscious state follows.
— Muscle rigidity develops, leading to respiratory compromise,
hypoxia, respiratory acidosis, hyperthermia and
rhabdomyolysis.
— Autonomic instability is demonstrated by swings from
hypertension to hypotension.
— Disseminated intravascular coagulation (DIC) and multiple
organ failure may occur.
— Even with optimal supportive care, intoxication may last
several days.
• Classically described MAOI adverse reactions
— Serotonin syndrome
— Tyramine reaction: after the ingestion of a tyramine-
containing food (e.g. cheese) patients complain of
severe occipital headache, associated with pronounced
hypertension, sweating, agitation, mydriasis and sometimes
chest pain. Complications of acute hypertensive crises
include:
– Intracranial haemorrhage
– Rhabdomyolysis
– Acute renal failure
– DIC.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• Serial ECGs (moclobemide)
— Mild QT prolongation is described following moclobemide
overdose. A 12-lead ECG is reviewed at presentation and at
6 hours. If the QT is >450 ms, further monitoring is indicated.
• EUC, FBC, CK, troponin, arterial blood gases, chest X-ray, cranial
CT scan, EEG
MANAGEMENT
SPECIFIC TOXINS

• A basic level of supportive care and monitoring is sufficient for
pure moclobemide overdose.
• Serotonin syndrome and severe sympathomimetic toxicity are
potentially life-threatening emergencies and managed in an area
equipped for cardiorespiratory monitoring and resuscitation.
• Attention to airway, breathing and circulation are paramount (see
Chapter 1.2: Resuscitation).
302
• Hypertension and tachycardia are usually controlled with titrated
IV benzodiazepines. Severe hypertension (including tyramine
30
reactions) may require parenteral vasodilator therapy. Caution is

2
required, as the onset of autonomic instability may rapidly

produce hypotension. Consider:
TOXICOLOGY HANDBOOK
— Titrated vasodilator infusion (sodium nitroprusside, glyceryl

trinitrate)
— α-antagonism (phentolamine 2–3-mg increments every 10–15
minutes until control achieved).
— Note: β-Adrenergic blockers are contraindicated as
unopposed α-agonist stimulation may result.
• Seizures and agitated delirium may be managed with
benzodiazepines, as outlined in Chapter 2.6: Seizures and
• Hyperthermia resulting from MAOI toxicity requires aggressive
therapy.
resuscitation.
— Temperature >39.5°C requires rapid treatment to prevent
multiple organ failure and neurological injury. Paralysis,
intubation, ventilation and active cooling are indicated.
• Life-threatening serotonin syndrome requires specific care,
including paralysis and intubation and ventilation to avoid fatalities
(see Chapter 2.8: Serotonin syndrome).
Decontamination
• Moclobemide overdose has a good prognosis with standard
supportive care. Decontamination is not indicated.
ERRNVPHGLFRVRUJ
• Patients who are alert and cooperative and who have ingested
>1 mg/kg of tranylcypromine or >2 mg/kg of phenelzine are given
50 g oral activated charcoal if they present within 2 hours.
Activated charcoal is contraindicated in the symptomatic patient
due to the potential for imminent deterioration of conscious state
and seizures.
Antidotes
• A trial of cyproheptadine is indicated in patients with symptoms
consistent with mild-to-moderate serotonin syndrome refractory
to benzodiazepines (see Chapter 4.3: Cyproheptadine).
SPECIFIC TOXINS
• Patients who are clinically well without features of serotonin
toxicity at 12 hours may be discharged. Discharge should not
occur at night.
• Patients with symptomatic moclobemide overdose are
managed supportively in a ward environment following a period
of 6 hours close observation. When the patient is clinically well,
ambulant, passing urine, eating and drinking, discharge may
303
occur.
• Patients with severe serotonin syndrome or phenelzine/
tranylcypromine overdose usually require management in an
TOXICOLOGY HANDBOOK
HANDY TIP
• Hyperthermia in the setting of MAOI toxicity requires rapid and
aggressive therapy.
PITFALLS
• Failure to observe a patient for a sufficient period of time
following deliberate self-poisoning with phenelzine or
tranylcypromine, or following moclobemide overdose in
combination with other serotonergically active agents.
CONTROVERSY
• The role of specific serotonin antagonists in the management of
MAOI toxicity.
Presentations
Moclobemide 150 mg tablets (60)
Moclobemide 300 mg tablets (60)
Phenelzine sulfate 15 mg tablets (100)
Selegiline hydrochloride 5 mg tablets (100)
Tranylcypromine sulfate 10 mg tablets (50)
References
Downes MA, Whyte IM, Isbister GK. QTc abnormalities in deliberate self-poisoning with
moclobemide. Internal Medicine Journal 2005; 35:388–391.
ERRNVPHGLFRVRUJ
Isbister GK, Hackett LP, Dawson AH et al. Moclobemide poisoning: toxicokinetics and
occurrence of serotonin toxicity. British Journal of Clinical Pharmacology 2003;
56(4):441–450.
Kaplan RF, Feinglass NG, Webster W. Phenelzine overdose treated with dantrolene
sodium. Journal of the American Medical Association 1986; 255:642–644.
Mills KC. Monoamine oxidase inhibitor toxicity. Emergency Medicine 1993; 15:58–71
3.54 NEW ORAL ANTICOAGULANTS

Apixaban, Dagibatran, Rivaroxaban
These new oral anticoagulants (NOACs) are increasingly prescribed to
treat thromboembolic disease and reduce risk of stroke in atrial
SPECIFIC TOXINS
fibrillation. Most NOAC-related bleeding occurs in the context of

therapeutic administration, often as a result of drug interactions, renal
failure or significant underlying pathology predisposing to bleeding
complications. Clinical experience with deliberate self-poisoning with
NOACs is limited. Assessment and management is further complicated
by the poor correlation of anticoagulant activity with classic coagulation
tests and the lack of reliable strategies to reverse anticoagulation.
RISK ASSESSMENT
304
• NOACs are potent anticoagulant agents and overdose with any
30
amount could result in clinically significant bleeding.

4
• Classic coagulation tests correlate poorly with the anticoagulant

TOXICOLOGY HANDBOOK
effect of these agents and have a limited role in refining risk

assessment.
• Children: there are no published reports of NOAC overdose in
children but accidental ingestion of even 1 or 2 tablets will
produce significant anticoagulation and an undefined risk of
bleeding.
Toxic mechanism
Dagibatran is a direct competitive inhibitor of both free and fibrin-bound thrombin.
Apixaban and rivaroxaban are direct factor Xa inhibitors. They inhibit free factor Xa as
well as factor Xa bound in the prothrombinase complex or associated with thrombin.
Toxicokinetics
Dagibatran has a bioavailability of only 6% following oral administration but this is
increased to 75% if the granules are removed from the capsules prior to ingestion. Peak
concentrations occur 2–4 hours after ingestion. Dagibatran is metabolised by the liver to
form active metabolites. Volume of distribution is 50–70 L and protein binding is 35%.
Elimination is predominantly renal with a terminal elimination half-life of 12–24 hours. This
is prolonged in the presence of renal impairment.
Apixaban and rivaroxaban have similar kinetics. Bioavailability is >50% following oral
administration. Peak concentrations are reached 3–4 hours after ingestion. Volumes of
distribution are relatively small (<50 L) and they are highly protein bound. Elimination is
renal and hepatic with terminal elimination half-lives of 5–14 hours but increased in the
presence of renal impairment.
CLINICAL FEATURES
• Ingestion of these agents does not cause clinical manifestations
unless complicated by bleeding.
ERRNVPHGLFRVRUJ
• Coagulopathy complicated by active bleeding manifests as
bruising, petechiae or purpural rashes, gingival bleeding,
epistaxis, gastrointestinal bleeding or haematuria.
• In the absence of co-ingestants, the presence of altered mental
status or seizures is suggestive of intracranial bleeding.
INVESTIGATIONS
• FBC
• EUC
• Serum calcium
SPECIFIC TOXINS
• Liver function tests
• Blood group and antibody screen
• Coagulation studies
— The effects of NOACs on commonly available coagulation
tests are variable (see Table 3.54.1) and do not correlate well
with drug levels or risk of bleeding.
— More sensitive assay are useful (see Table 3.54.1) but less
readily available.
305
MANAGEMENT
TOXICOLOGY HANDBOOK
• If active bleeding is evident:
— Apply local control measures – compression, suturing.
— Institute haemodynamic support including fluid resuscitation
to maintain good urine output.
— Give blood products as indicated.
— Administer coagulation factors as per local protocols and
availability (consult haematology service early).
Decontamination
• Following deliberate self-poisoning in co-operative patients
presenting within 4 hours of ingestion, administer 50 g oral
activated charcoal.
• Dabigatran is effectively removed by haemodialysis. This
intervention should be considered early in acute dabigatran
overdose or the patient with dabigatran-related haemorrhage in
the presence of impaired renal function.
• Haemodialysis is not useful in apixaban or rivaroxaban overdose
or toxicity.
Antidotes
• There are currently no specific antidotes.
ERRNVPHGLFRVRUJ
TABLE 3.54.1 Effects of NOACs on coagulation studies
Factor Xa inhibitor
effect (apixaban,
Parameter Dabigatran effect rivaroxaban)
INR Mild prolongation Variable
aPTT Prolonged but poor Variable

correlation with drug
concentration
aPTT >90 seconds suggests
high drug level
Normal aPTT suggests
SPECIFIC TOXINS
minimal drug present
Thrombin Very sensitive Not useful

clotting time Normal value excludes
(TT, TCT) presence of drug
Exceeds measurement time
of coagulometer at high
concentration
306 Haemoclot Useful to derive levels Not useful
30
assay (dilute
6
thrombin time)
TOXICOLOGY HANDBOOK
Factor IIa Best correlation with Not useful

assay bleeding risk
Factor Xa Not useful Good correlation

assay with levels
Notes:
1 Combination of INR >2 and aPTT >90 seconds suggests high plasma
levels of dabigatran.
2 Normal INR and normal aPTT suggest low plasma levels of dabigatran.
3 Combination of normal PT and aPTT suggests low plasma levels of
apixaban and rivaroxaban.
4 Factor IIa, Xa and Haemoclot assays are available in few hospitals and
can take more than 24 hours to perform.
5 Thromboelastography is effective at measuring anticoagulant activity of
NOACs but specific assays have not yet been developed.
• Traditional reversal agents do not effectively reverse

anticoagulation from these agents. Various combinations of
recombinant factor VIIa, factor VIII inhibitor bypass activity
(FEIBA), prothrombin complex concentrates, tranexamic acid and
fresh frozen plasma (FFP) have been recommended in institutional
protocols.

• All patients who overdose on NOACs are admitted to hospital for
observation and serial coagulation studies until normalised.
ERRNVPHGLFRVRUJ
• All patients with NOAC-related bleeding are admitted to hospital
for active treatment as above.
• Dagibatran overdose must be managed in a hospital with capacity
for haemodialysis.
• Following dabigatran overdose, patients are medically cleared if
the INR and aPTT remain normal at 12 hours post ingestion.
• Following factor Xa inhibitor overdose, patients are medically
cleared if the PT and aPTT remain normal at 12 hours post
ingestion.
HANDY TIPS
• There is no evidence that administration of reversal agents in the
absence of bleeding has any beneficial effects.
•
SPECIFIC TOXINS
Do not rely on point-of-care (POC) coagulation testing. Correlation
with NOAC levels or bleeding risk is not validated.
PITFALLS
• Failure to admit and monitor patients who have ingested small
overdoses of any NOAC.
• Failure to prevent falls in patients with significant anticoagulation.
• Administration of coagulation factors in the absence of significant
bleeding. This is associated with a risk of thromboembolic
complications.
307
CONTROVERSIES
TOXICOLOGY HANDBOOK
• Administration of reversal agents in the absence of active
bleeding. There is no evidence that this intervention is associated
with clinical benefit.
• The role of early dialysis following dabigaran overdose in the
absence of active bleeding.
Presentations
Dabigatran etexilate 75 mg capsules (10, 60)
Apixaban 2.5 mg tablets (20, 30, 60)
Apixaban 5 mg tablets (60)
Rivaroxaban 10 mg tablets (10, 15, 30, 100)
Rivaroxaban 15 mg (28, 42)
Rivaroxaban 20 mg (28)
References
Chiew AL, Khamoudes D, Chan BS. Use of continuous veno-venous haemodiafiltration
therapy in dabigatran overdose. Clinical Toxicology 2014; 52:283–287.
Koscielny J, Rutkauskaite E. Rivaroxaban and hemostasis in emergency care. Emergency
Medicine International 2014; Feb 20 [Epub ahead of print].
Kumar R, Smith RE, Henry BL. A review of and recommendations for the management of
patients with life-threatening dabigatran-associated hemorrhage: a single-center
university hospital experience. J Intensive Care Medicine 2014; Mar 25 [Epub ahead
of print].
Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Practice
and Research in Clinical Haematology 2013; 26:191–202.
Pernod G, Albaladejo P, Godier A. Management of major bleeding complications and
emergency surgery in patients on long-term treatment with direct oral anticoagulants,
ERRNVPHGLFRVRUJ
thrombin or factor-Xa inhibitors: proposals of the Working Group on Perioperative
Haemostasis (GIHP) – March 2013. Archives of Cardiovascular Disease 2013;
106:382–393.
Wood P. New oral anticoagulants: an emergency department overview. Emergency
Medicine Australasia 2013; 25:503–514.
3.55 NON-STEROIDAL ANTI-INFLAMMATORY

DRUGS (NSAIDs)
Celecoxib, Diclofenac, Etoricoxib, Ibuprofen, Indomethacin, Ketoprofen,
Ketorolac, Mefenamic acid, Meloxicam, Naproxen, Parecoxib, Piroxicam,
Sulindac, Tiaprofenic acid
SPECIFIC TOXINS
Overdose with any of the NSAIDs, unless the ingestion is massive, is

benign. Management is symptomatic and supportive. Ibuprofen accounts
for over two-thirds of NSAID deliberate self-poisoning cases.
RISK ASSESSMENT
• Overdose with these agents is generally benign, even following
large ingestions. Dose-related risk assessment is best defined for
ibuprofen (see Table 3.55.1).
308
30
TABLE 3.55.1 Dose-related risk assessment: Ibuprofen

8
TOXICOLOGY HANDBOOK
Dose Effect
<100 mg/kg Asymptomatic
100–300 mg/kg Mild GI and CNS symptoms
>300 mg/kg Risk of multi-system organ dysfunction
• Massive overdose is associated with severe multi-system organ

dysfunction including shock, coma, seizure, acute renal failure
and metabolic acidosis. Fatalities are reported.
• Overdose with any amount of mefenamic acid is commonly
associated with self-limiting seizures.
• Children: significant symptoms usually are not observed until the
dose ingested exceeds 300 mg/kg of ibuprofen (or equivalent of
other NSAID). Minor unintentional ingestion of <100 mg/kg of
ibuprofen does not require referral to hospital for assessment or
observation. All mefanamic acid ingestions are referred to hospital
because of the seizure risk.
Toxic mechanism
NSAIDs exert their pharmacological effects through the competitive inhibition of
cyclooxygenase-1 and -2 and consequent blockade of prostaglandin synthesis. The
NSAIDs are directly irritant to the gastrointestinal tract. Prostaglandin inhibition leads to
renal glomerular vasoconstriction and mild reversible renal dysfunction. Bleeding time is
prolonged due to inhibition of thromboxane A2 production. The exact mechanism of the
other effects is unclear.
ERRNVPHGLFRVRUJ
Toxicokinetics
NSAIDs are rapidly absorbed following oral administration. Most are highly protein
bound and have small volumes of distribution. They undergo hepatic metabolism
and metabolites are excreted in the urine. Most agents have elimination half-lives of
less than 4 hours (naproxen and piroxicam have half-lives of 12 and 45 hours,
respectively).
CLINICAL FEATURES
• Following acute overdose, most patients are asymptomatic or
experience minor self-limiting gastrointestinal symptoms such as
nausea, vomiting and epigastric discomfort.
• Minor CNS symptoms such as lethargy and drowsiness are
sometimes observed.
• Massive ibuprofen overdose can result in rapid onset of
SPECIFIC TOXINS
shock, coma, seizures, acute renal failure and metabolic
acidosis.
• Self-limiting seizures commonly occur within hours of mefenamic
acid overdose.
• Chronic use of ibuprofen is associated with renal tubular acidosis
and the potential for life-threatening hypokalaemia.
INVESTIGATIONS
Screening tests in deliberate self-poisoning 309
TOXICOLOGY HANDBOOK
• EUC, LFTs and FBC in symptomatic patients.
• An anion gap metabolic acidosis is commonly observed
and not of clinical importance. It usually resolves within
24–48 hours.
• NSAID serum levels are not routinely available and do not assist
in management.
MANAGEMENT
• Seizures and agitated delirium are managed with
benzodiazepines, as outlined in Chapter 2.6: Seizures and
Decontamination
• Oral activated charcoal is contraindicated following mefenamic
overdose because of the risk of imminent seizures.
Antidotes
• None available.
ERRNVPHGLFRVRUJ
• Children may be observed at home following possible
unintentional ingestion, unless symptoms occur.
• Adult patients following deliberate self-poisoning who are
asymptomatic with normal vital signs at 4 hours post ingestion
are fit for medical discharge.
• Symptomatic patients with mild-to-moderate gastrointestinal or
CNS symptoms may be managed supportively in a ward
environment. They are fit for medical discharge when ambulant,
passing urine, eating and drinking.
• Patients with significant CNS depression are admitted to an
intensive care unit for supportive care and monitoring.
SPECIFIC TOXINS
HANDY TIP
• Anticipate seizures following mefenamic acid overdose.
PITFALL
• Failure to anticipate the risk of multi-system organ dysfunction
following massive ingestion of these agents.
Preparations
310 Celecoxib 100 mg capsules (60) Ibuprofen 40 mg/mL oral liquid (30 mL,
Celecoxib 200 mg capsules (10, 30) 40 mL, 50 mL, 100 mL)
31
Diclofenac sodium 12.5 mg tablets (10, 20) Ibuprofen lysine 342 mg tablets (12, 36)
0
Diclofenac sodium 25 mg tablets (10, 20, Ibuprofen 200 mg/codeine phosphate

TOXICOLOGY HANDBOOK
30) 12.8 mg tablets (12, 24, 48, 96)

Diclofenac sodium 50 mg tablets (20) Ibuprofen 150 mg/paracetamol 500 mg
Diclofenac sodium 25 mg enteric coated tablets (10, 16, 30)
tablets (20, 30, 50) Ibuprofen 200 mg/pseudoephedrine
Diclofenac sodium 50 mg enteric coated hydrochloride 30 mg tablets (24)
tablets (50) Indomethacin 25 mg capsules (50, 90, 100)
Diclofenac sodium 50 mg oral liquid as Indomethacin 100 mg suppositories (20,
powder (21 sachets) 40)
Diclofenac sodium 12.5 mg suppositories Indomethacin sodium trihydrate 1 mg
(10) powder, injectable
Diclofenac sodium 25 mg suppositories Ketoprofen 200 mg sustained-release
(10) pellet capsules (28)
Diclofenac sodium 50 mg suppositories Ketoprofen 100 mg suppositories (20, 40)
(10) Ketoprofen 2.5% gel (30 g, 60 g)
Diclofenac sodium 100 mg suppositories Ketorolac trometamol 10 mg tablets (20)
(20, 40) Ketorolac trometamol 10 mg/mL injectable
Diclofenac sodium 50 mg/misoprostol 200 (1 mL)
microgram tablets (60) Ketorolac trometamol 30 mg/mL injectable
Diclofenac 1% gel (20 g, 50 g, 100 g, 150 g) (1 mL)
Etoricoxib 30 mg (30) Mefenamic acid 250 mg capsules (20, 50)
Etoricoxib 60 mg (30) Meloxicam 7.5 mg tablets (30)
Etoricoxib 120 mg (10) Meloxicam 15 mg tablets (30)
Ibuprofen 100 mg tablets (20) Meloxicam 7.5 mg capsules (30)
Ibuprofen 200 mg tablets (12, 20, 24, 36, Meloxicam 15 mg capsules (30)
40, 48, 50, 96) Naproxen 250 mg tablets (50, 100)
Ibuprofen 400 mg tablets (12, 24, 30, 90) Naproxen 500 mg tablets (50)
Ibuprofen 200 mg capsules (10, 20, 40, 90) Naproxen 750 mg sustained-release
Ibuprofen 400 mg capsules (10) tablets (28)
Ibuprofen 5% gel (30 g, 50 g, 100 g) Naproxen 1000 mg sustained-release
Ibuprofen 20 mg/mL oral liquid (100 mL, tablets (28)
200 mL) Naproxen 25 mg/mL oral liquid (474 mL)
ERRNVPHGLFRVRUJ
Naproxen sodium 275 mg tablets (12, 24) Piroxicam 20 mg tablets (25)
Naproxen sodium 550 mg tablets (50) Piroxicam 10 mg capsules (50)
Naproxen 500 mg/esomeprazole 20 mg Piroxicam 20 mg capsules (25)
enteric coated tablets (60) Piroxicam 0.5% gel (25 g, 50 g)
Parecoxib sodium 40 mg powder + Sulindac 100 mg tablets (50)
solvent, injectable Sulindac 200 mg tablets (50)
Piroxicam 10 mg tablets (50) Tiaprofenic acid 300 mg tablets (60)
References
Balali-Mood M, Critchley JA, Proudfoot AT et al. Mefenamic acid overdose. Lancet 1981;
1:1354–1356.
Hall AH, Smolinske SC, Conrad FL et al. Ibuprofen overdose: 126 cases. Annals of
Hall AH, Smolinske SC, Stover B et al. Ibuprofen overdose in adults. Journal of
SPECIFIC TOXINS
McElwee NE, Veltri JC, Bradford DC et al. A prospective, population-based study of
acute ibuprofen overdose: complications are rare and routine serum levels not
warranted. Annals of Emergency Medicine 1990; 19(6):657–662.
Ng JL, Morgan DJR, Loh NKM et al. Life-threatening hypokalaemia associated with
ibuprofen-induced renal tubular acidosis. Medical Journal of Australia 2011;
194:313–316.
3.56 OLANZAPINE
311
Deliberate self-poisoning with this second-generation atypical
antipsychotic agent is associated with sedation, delirium and coma in
TOXICOLOGY HANDBOOK
ascending doses. Thorough supportive care ensures a good outcome.
RISK ASSESSMENT
• Olanzapine overdose is associated with predictable dose-
dependent clinical features (see Table 3.56.1).
• Extrapyramidal effects are uncommon.
• Co-ingestion of ethanol or other sedative-hypnotic agents
increases the risk of coma.
• Children: the toxic dose is not clear. Ingestion of >0.5 mg/kg may
cause clinical features of intoxication including lethargy, agitation,
TABLE 3.56.1 Dose-related risk assessment: Olanzapine
Dose (adult) Effect
<40 mg Therapeutic sedation and antipsychotic effects
40–100 mg Mild-to-moderate sedation with possible

anticholinergic effects
100–300 mg Sedation with intermittent marked agitation
>300 mg Increasing sedation progressing to coma likely to

require intubation
Hypotension secondary to peripheral alpha
blockade
ERRNVPHGLFRVRUJ
tachycardia and extrapyramidal effects. Referral to hospital for
monitoring and supportive care is warranted. Delayed
extrapyramidal effects may occur over the following days.
Toxic mechanism
Olanzapine is an antagonist at dopamine (D2), serotonin (particularly 5-HT2), histamine
(H1), muscarinic (M1) and peripheral alpha (α) receptors.
Toxicokinetics
Olanzapine is well absorbed after oral or sublingual administration. The volume of
distribution is 10–20 L/kg. It undergoes hepatic metabolism by oxidative (cytochromes
P450 1A2 and 2D6) and conjugative (glucuronidation) pathways to inactive water-soluble
metabolites. There is a large first-pass effect after oral dosing.
SPECIFIC TOXINS
CLINICAL FEATURES
• Onset of clinical features of intoxication occurs within 2–4 hours.
• Sedation, ataxia, miosis, orthostatic hypotension and tachycardia
are common.
• Fluctuating mental status with intermittent agitated delirium
occurs with moderate doses, usually lasting less than 24 hours.
Urinary retention frequently complicates this presentation.
• Coma when it occurs following large ingestions lasts from 18 to
48 hours.
312 • Non-specific ST-T wave changes occur in 15% of overdoses, but
clinically significant QT prolongation is rare.
31
•
2
Extrapyramidal effects are uncommon.

• Seizures are rare.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
• Serial ECGs
— An ECG is performed at presentation and at 6 hours. If the
ECG is normal at that time, further ECG monitoring may be
ceased in the unintubated patient.
— In the intubated patient, 12-lead ECGs are assessed for QT
prolongation every 4 hours until clinical improvement occurs.
MANAGEMENT
• Intubation and ventilation may be required if significant sedation
occurs.
• Severe agitated delirium is managed, as outlined in Chapter 2.7:
Delirium and agitation.
• Monitor for urinary retention and insert an indwelling urinary
catheter if required.
ERRNVPHGLFRVRUJ
Decontamination
• Oral activated charcoal is not indicated, because the onset of
sedation and coma occurs early and supportive care ensures a
good outcome.
Antidotes
• None available.
• All paediatric patients are observed in hospital following possible
unintentional ingestion of >0.5 mg/kg. If they remain clinically well
SPECIFIC TOXINS
without sedation at 4 hours following ingestion they can be safely
discharged. Parents are advised that abnormal (extrapyramidal)
movements sometimes occur up to 3 days after ingestion.
• Patients with mild sedation, normal blood pressure and normal
12-lead ECG may be managed supportively in a ward
environment. Medical discharge occurs when the patient is
clinically well, ambulant, passing urine, eating and drinking.
• Patients with significant agitation or delirium, and those requiring
intubation, require admission to a high-dependency or intensive
care unit, often for up to 48 hours.
313
HANDY TIP
TOXICOLOGY HANDBOOK
• Benzodiazepines are first-line agents for the management of
olanzapine-induced agitated delirium. However, subsequent
fluctuations in mental status may mandate intubation and
ventilation.
PITFALL
• Undetected urinary retention contributes to agitation and is
managed with an indwelling catheter.
CONTROVERSIES
• The role of physostigmine in the management of agitated delirium.
It is not clear that the delirium is entirely of anticholinergic origin.
• Physostigmine is also reported to reverse olanzapine-induced
coma. The efficacy, clinical utility and indications for
physostigmine in this situation are undefined.
Presentations
Olanzapine 2.5 mg tablets (28)
Olanzapine 5 mg tablets (28)
Olanzapine 7.5 mg tablets (28)
Olanzapine 5 mg wafers (28)
Olanzapine 10 mg powder, injectable
ERRNVPHGLFRVRUJ
Olanzapine pamoate monohydrate 210 mg powder + solvent, injectable
References
Burns MJ. The pharmacology and toxicology of atypical antipsychotic agents. Journal of
Palenzona S, Meier PJ, Kupferschmidt H et al. Clinical picture of olanzapine poisoning
with special reference to fluctuating mental status. Journal of Toxicology – Clinical
Toxicology 2004; 42(1):27–32.
3.57 OPIOIDS
SPECIFIC TOXINS
Buprenorphine, Codeine, Dextropropoxyphene, Fentanyl, Heroin,

Hydromorphone, Methadone, Morphine, Oxycodone, Pethidine
Opioid intoxication causes CNS and respiratory depression. Death is due
to respiratory failure. Good supportive care ensures survival. The specific
antidote, naloxone, can assist the management of airway and breathing.
Some opioids possess unexpected toxic effects (e.g.
314 dextropropoxyphene).
31
4
RISK ASSESSMENT
•
TOXICOLOGY HANDBOOK
Life-threatening CNS and respiratory depression frequently occur

just above the analgesic dose.
• Opioid use by naïve patients (no tolerance) or co-ingestion of
other CNS depressants (antidepressants, benzodiazepines,
ethanol) increases the severity of CNS depression and the
likelihood of a fatal outcome without supportive care.
• Certain agents have specific risk assessments based on particular
toxicities (see Table 3.57.1).
• Children: opioid intoxication is the leading cause of death by
poisoning in children. Ingestion of a single opioid tablet or a
TABLE 3.57.1 Opioid risk assessment: Special cases
Drug Effect
Dextropropoxyphene 10 mg/kg likely to cause symptoms

20 mg/kg may cause CNS
depression, seizures and
cardiac dysrhythmias (fast
sodium channel blocking effect)
Methadone and oxycodone QT prolongation
Pethidine Repeated therapeutic doses are

associated with seizures
Implicated in serotonin syndrome
ERRNVPHGLFRVRUJ
mouthful of methadone syrup can cause respiratory arrest. More
than 2 mg/kg of codeine may cause symptoms in children and
>5 mg/kg can cause respiratory arrest.
Toxic mechanism
Agonist activity at µ-receptors is responsible for euphoria, analgesia, physical
dependence, sedation and respiratory depression. Multiple other opioid actions are
responsible for side effects such as nausea and vomiting (dopamine receptors),
constipation (peripheral µ-receptors in the gut wall), pruritus (histamine release) and
seizures.
Toxicokinetics
Oral absorption of opioids is variable. Most, with the exception of controlled-release
preparations, are absorbed rapidly. Volumes of distribution are usually large (e.g. codeine
2.6 L/kg; methadone 3.6 L/kg; morphine 3.4 L/kg). Most undergo hepatic metabolism to
SPECIFIC TOXINS
form metabolites that are excreted in the urine, some of which are active. Morphine, for
example, is one of three active metabolites of codeine.
CLINICAL FEATURES
• The classic opioid toxidrome consists of:
— CNS depression
— Respiratory depression (rate and depth of respirations)
— Miosis.
• The duration of effects depends on the pharmacokinetics of the 315
individual agent. Heroin intoxication is typically short (e.g. less
than 6 hours), while methadone and oxycodone intoxication may
last more than 24 hours.
TOXICOLOGY HANDBOOK
• Death is caused by loss of airway protective reflexes and apnoea.
• Nausea and vomiting may occur, promoting pulmonary aspiration.
• Bradycardia is common. Tachycardia may occur as a response to
hypoxia and hypercarbia.
• Hypothermia, skin necrosis, compartment syndrome,
rhabdomyolysis and hypoxic brain injury may complicate
prolonged non-lethal intoxication.
• Methadone and oxycodone are associated with QT prolongation
although torsades de pointes is rare.
• Dextropropoxyphene intoxication is also associated with seizures,
hypotension and ventricular dysrhythmias.
• Pethidine is associated with serotonin syndrome.
INVESTIGATIONS
Specific investigations as indicated:
• Specific blood levels and urine screening do not assist clinical
management.
• Specific investigations are only indicated to diagnose and assess
secondary complications.
MANAGEMENT
ensure the survival of the vast majority of patients.
ERRNVPHGLFRVRUJ
• These priorities are managed along conventional lines, as outlined
• In the rare event of ventricular dysrhythmias in
dextropropoxyphene intoxication, resuscitation includes serum
alkalinisation by the administration of IV bolus sodium
bicarbonate, as outlined in Chapter 4.24: Sodium bicarbonate.
Decontamination
• Opioid intoxication is associated with CNS and respiratory
depression, and vomiting. A good outcome is expected with
supportive care and, possibly, antidote administration. Therefore,
SPECIFIC TOXINS
activated charcoal is not routinely indicated.

• Oral activated charcoal may reduce length of stay if administered
to a patient presenting early after overdose with controlled-
release morphine tablets.
Antidotes
316 • Respiratory and CNS depression can be reversed with titrated
doses of naloxone (see Chapter 4.18: Naloxone). Continuous
31
6
naloxone infusion may be required following overdose of

long-acting opioids or slow-release preparations.
TOXICOLOGY HANDBOOK

• The period of observation required to detect CNS depression
varies with the opioid. For most standard-release oral
preparations 4 hours is sufficient.
• A patient who ingests controlled-release opioid preparations must
be observed for at least 12 hours before medical clearance.
• Following ingestion of standard preparations, patients with mild
sedation who have not required naloxone may be managed in a
ward environment after an initial observation period of 4 hours.
• Any child who has potentially ingested an opioid (unless <2 mg/kg
of codeine) is admitted for 12 hours of close observation in an
area equipped and staffed to detect and manage respiratory
depression. Discharge must not occur at night.
• Patients with significant CNS depression requiring intubation or
naloxone infusion require admission to a high-dependency or
HANDY TIPS
• Patients must be admitted to an area with staff and resources
capable of detecting respiratory depression.
• Appraise staff of the features of opioid intoxication for which the
patient is being observed (CNS depression and decreased
respiratory rate).
• Respiratory depression can be delayed up to 12 hours following
controlled-release morphine or oxycodone overdose.
ERRNVPHGLFRVRUJ
• Respiratory rate should be measured while the patient is sleeping
or otherwise undisturbed.
• Opioid intoxicated patients are observed on room air with
saturation monitoring, provided aspiration has not occurred. Poor
oxygenation saturations are likely to be detected earlier than
respiratory depression.
PITFALLS
• Failure to recognise the potential lethality of unintentional
paediatric ingestion of opioids.
• Failure to detect opioid-induced respiratory depression due to
inadequate observation (in-hospital deaths have occurred).
Presentations
SPECIFIC TOXINS
Buprenorphine Codeine phosphate 12.8 mg/ibuprofen
Buprenorphine 5 mg transdermal patches 200 mg tablets (12, 24, 48)
Buprenorphine 10 mg transdermal Codeine phosphate 6 mg/paracetamol
patches 500 mg/pseudoephedrine 30 mg
Buprenorphine 20 mg transdermal tablets (16, 24, 32, 48)
patches Codeine phosphate 9 mg/paracetamol
Buprenorphine 2 mg/naloxone 0.5 mg 500 mg/pseudoephedrine 30 mg
sublingual tablets (7, 28) tablets (24, 30, 48, 60)
Buprenorphine 8 mg/naloxone 2 mg Codeine phosphate 8 mg/paracetamol
sublingual tablets (7, 28) 500 mg/doxylamine succinate 5 mg 317
Buprenorphine 0.2 mg sublingual tablets tablets (20, 24)
(50) Codeine phosphate 9.6 mg/paracetamol
Buprenorphine 0.4 mg sublingual tablets 500 mg/doxylamine succinate 5.1 mg
TOXICOLOGY HANDBOOK
(7) tablets (10, 20)
Buprenorphine 2 mg sublingual tablets (7) Codeine phosphate 10 mg/paracetamol
Buprenorphine 8 mg sublingual tablets (7) 500 mg/doxylamine succinate 5.1 mg
Buprenorphine injection 300 tablets (20)
microgram/1 mL Codeine phosphate 10 mg/paracetamol
Codeine 500 mg/doxylamine succinate 2 mg
Codeine phosphate 30 mg tablets (20, capsules (20)
100) Codeine phosphate 9.75 mg/paracetamol
Codeine phosphate 5 mg/1 mL (100 mL) 450 mg/doxylamine succinate 5 mg
Codeine phosphate 19.2 mg/ tablets (20)
pseudoephedrine HCl 60 mg/ethanol Codeine phosphate 9.75 mg/paracetamol
6%/10 mL (200 mL) 450 mg/doxylamine succinate 5 mg
Codeine phosphate 15 mg/phenylephrine caplets (20)
HCl 5 mg/pseudoephedrine HCl Codeine phosphate 30 mg/paracetamol
45 mg/guaifenesin 60 mg/ammonium 450 mg/doxylamine succinate 5 mg
chloride 200 mg/10 mL (200 mL) tablets (20)
Codeine phosphate 14.9 mg/ Codeine phosphate 10 mg/paracetamol
pseudoephedrine HCl 60 mg/10 mL 500 mg tablets (24, 48, 96)
(200 mL) Codeine phosphate 8 mg/paracetamol
Codeine phosphate 8 mg/aspirin 300 mg 500 mg tablets (12, 20, 24, 48, 50, 96,
tablets (20, 50, 100) 100)
Codeine phosphate 8 mg/aspirin 250 mg Codeine phosphate 30 mg/paracetamol
tablets (24, 96) 500 mg tablets (20, 50)
Codeine phosphate 8 mg/aspirin 325 mg Codeine phosphate 9.6 mg/paracetamol
tablets (20, 50, 100) 500 mg caplets (12, 20, 24, 40, 48)
tablets (24, 48) 500 mg caplets (12)
Codeine phosphate 9.5 mg/aspirin 500 mg Codeine phosphate 15 mg/paracetamol
tablets (24) 500 mg tablets (20, 50)
tablets (20, 50) 120 mg/5 mL (100 mL, 200 mL)
ERRNVPHGLFRVRUJ
Codeine phosphate 5 mg/paracetamol Morphine sulfate 20 mg tablets (20)
120 mg/promethazine 6.5 mg/5 mL Morphine sulfate 30 mg tablets (20)
(100, 200 mL) Morphine sulfate 5 mg controlled-release
Dextropropoxyphene tablets (20)
Dextropropoxyphene 32.5 mg/paracetamol Morphine sulfate 10 mg controlled-release
325 mg capsules (20) tablets (20, 60)
Dextropropoxyphene 32.5 mg/paracetamol Morphine sulfate 15 mg controlled-release
325 mg tablets (20) tablets (20, 60)
Dextropropoxyphene 100 mg capsules (10) Morphine sulfate 30 mg controlled-release
Fentanyl tablets (20, 60)
Fentanyl citrate 200 microgram lozenges Morphine sulfate 60 mg controlled-release
(3) tablets (20, 60)
Fentanyl citrate 400 microgram lozenges Morphine sulfate 100 mg controlled-
(3) release tablets (20, 60)
Fentanyl citrate 600 microgram lozenges Morphine sulfate 200 mg controlled-
SPECIFIC TOXINS
(3) release tablets (20, 60)

Fentanyl citrate 800 microgram lozenges Morphine sulfate 20 mg controlled-release
(3) granules for reconstitution (20)
Fentanyl 12 microgram/hour (2.1 mg) Morphine sulfate 30 mg controlled-release
transdermal patches granules for reconstitution (20)
Fentanyl 25 microgram/hour (2.5 mg) Morphine sulfate 60 mg controlled-release
transdermal patches granules for reconstitution (20)
Fentanyl 25 microgram/hour (4.2 mg) Morphine sulfate 100 mg controlled-
transdermal patches release granules for reconstitution (20)
Fentanyl 50 microgram/hour (5 mg) Morphine sulfate 200 mg controlled-
318 transdermal patches release granules for reconstitution (20)
Fentanyl 50 microgram/hour (8.4 mg) Morphine sulfate 30 mg modified-release
31
8
transdermal patches capsules (10)

TOXICOLOGY HANDBOOK

Fentanyl 100 microgram/hour (10 mg) Morphine sulfate 120 mg modified-release
Fentanyl 100 microgram/hour (16.8 mg) Morphine sulfate 10 mg sustained-release
transdermal patches pellet capsules (20, 60)
Fentanyl citrate 100 microgram/2 mL Morphine sulfate 20 mg sustained-release
transdermal ampoules pellet capsules (20, 60)
Fentanyl citrate 500 microgram/10 mL Morphine sulfate 50 mg sustained-release
ampoules pellet capsules (20, 60)
Fentanyl citrate 1000 microgram/20 mL Morphine sulfate 100 mg sustained-
ampoules release pellet capsules (20, 60)
Hydromorphone Morphine sulfate 5 mg/1 mL ampoules
Hydromorphone 2 mg tablets (20) Morphine sulfate 10 mg/1 mL ampoules
Hydromorphone 1 mg/mL (473 mL) Morphine hydrochloride 1 mg/mL
Hydromorphone 2 mg/1 mL ampoules (200 mL)
Hydromorphone 10 mg/1 mL ampoules Morphine hydrochloride 2 mg/1 mL
Hydromorphone 50 mg/5 mL ampoules (200 mL)
Hydromorphone 500 mg/50 mL vials Morphine hydrochloride 5 mg/1 mL
Methadone (200 mL)
Methadone hydrochloride 5 mg/mL Morphine hydrochloride 10 mg/1 mL
(200 mL, 1000 mL) (200 mL)
Methadone hydrochloride 10 mg tablets Morphine tartrate 120 mg/1.5 mL
(20) ampoules
Methadone hydrochloride 10 mg/1 mL Morphine tartrate 400 mg/5 mL ampoules
ampoules Oxycodone
Morphine Oxycodone hydrochloride 5 mg capsules
Morphine sulfate 10 mg tablets (20) (20)
ERRNVPHGLFRVRUJ
Oxycodone hydrochloride 10 mg capsules Oxycodone hydrochloride 10 mg/
(20) naloxone 5 mg controlled release
Oxycodone hydrochloride 20 mg capsules tablets (28)
(20) Oxycodone hydrochloride 20 mg/
Oxycodone hydrochloride 5 mg tablets naloxone 10 mg controlled release
(20, 60) tablets (28)
Oxycodone hydrochloride 10 mg tablets Oxycodone hydrochloride 40 mg/
(20, 60) naloxone 20 mg controlled release
Oxycodone hydrochloride 20 mg tablets tablets (28)
(20, 60) Pethidine
Oxycodone hydrochloride 40 mg tablets Pethidine hydrochloride 50 mg/1 mL
(20, 60) ampoules
Oxycodone hydrochloride 80 mg tablets Pethidine hydrochloride 75 mg/1.5 mL
(20, 60) ampoules
Oxycodone hydrochloride 30 mg Pethidine hydrochloride 100 mg/2 mL
SPECIFIC TOXINS
suppositories (12) ampoules
Oxycodone hydrochloride 5 mg/5 mL Pethidine hydrochloride 500 mg/10 mL
(250 mL) ampoules
Oxycodone hydrochloride 5 mg/naloxone
2.5 mg controlled release tablets (28)
Reference
Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers.
319
3.58 ORGANOCHLORINES
TOXICOLOGY HANDBOOK
Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin,
Endosulfan, Endrin, Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan,
Lindane, Methoxychlor
Chlorinated pesticides are widely used in agriculture. Lindane is used
medically as a treatment for lice infestations. Acute ingestion or
repeated large dermal exposure causes neurological toxicity, including
seizures and coma. Rarely, ventricular dysrhythmias occur due to
sensitisation of the myocardium to catecholamines. Management is
supportive.
RISK ASSESSMENT
• The risk assessment for lindane is relatively well documented (see
Table 3.58.1). There is a paucity of data regarding acute and
chronic exposures to other organochlorines. As a general guide
TABLE 3.58.1 Dose-related risk assessment: Lindane
Effect
Child Ingestion of >50 mg (5 mL of 1% solution) causes

symptoms
Adult Estimated mean lethal ingested dose is 125 mg/kg

Dose required to induce toxicity from dermal absorption
not defined
ERRNVPHGLFRVRUJ
endrin, aldrin, dieldrin and chlordane have the lowest LD50s in
animal models.
• Toxicity occurs in three main settings:
— Acute deliberate self-poisoning by ingestion – rapid onset of
neurological symptoms, seizures and coma
— Excessive dermal application or accidental ingestion of
lindane – agitation and seizures
— Occupational exposures via dermal or inhalational routes
– usually no acute symptoms.
• Children: ingestion is potentially life threatening. Topical lindane
used as a lice treatment can cause agitation and seizures,
particularly with repeat use or prolonged application.
SPECIFIC TOXINS
Toxic mechanism
Lindane and the cyclodienes (aldrin, dieldrin, heptachlor, endrin, chlordane, endosulfan)
are non-competitive antagonists acting at the chlorine ion channel of GABAA receptors.
DDT acts by inhibiting sodium channel closure following depolarisation. Both
mechanisms are neuroexcitatory.
Toxicokinetics
These agents are rapidly absorbed following ingestion. The degree of dermal absorption
depends on the agent, concentration, solvent (usually hydrocarbon) and skin integrity.
Lindane and the cyclodienes are well absorbed across skin. Organochlorines are highly
320 lipid soluble and widely distributed to fat stores. Accumulation may occur with repeated
occupational exposure. Organochlorines undergo hepatic microsomal metabolism prior
32
0
to elimination in the urine. They have non-linear kinetics, due to slow redistribution from
fat stores. Elimination of some organochlorines may take weeks to months.
TOXICOLOGY HANDBOOK
CLINICAL FEATURES
• Principal clinical features of toxicity are:
— Anxiety, agitation and confusion
— Perioral paraesthesia, fasciculation and myoclonic movements
— Seizures – these are usually of short duration but may be
recurrent
— Sedation and coma.
• Clinical features develop within 1–2 hours of acute ingestion and
over hours to days following excessive dermal application.
• Hypotension, cardiac dysrhythmias and ventricular ectopy are rare
complications of severe intoxication.
• Hypoxaemia and acidosis contribute to myocardial sensitisation
to catecholamines.
• Hepatitis and renal dysfunction are reported following acute
intoxication.
• Vomiting and aspiration may be complicated by a severe
chemical pneumonitis from the hydrocarbon vehicle in which
many of these agents are formulated.
INVESTIGATIONS
— Hypoxaemia and acidosis.
ERRNVPHGLFRVRUJ
— Increased ventricular ectopy may herald the onset of
ventricular tachydysrhythmias.
• EUC, liver function tests
— Hepatic and renal failure.
• Serum and fat organochlorine levels
— Not readily available and do not assist management.
MANAGEMENT
• Organochlorine poisoning is a potentially life-threatening
• Potential life threats that require immediate intervention include:
SPECIFIC TOXINS
— Coma (see Chapter 2.4: Coma)
— Seizures (see Chapter 2.6: Seizures)
— Ventricular dysrhythmias.
• Control agitation with carefully titrated doses of
benzodiazepines.
• Institute general supportive care, as outlined in Chapter 1.4:
Decontamination 321
• Resuscitation takes priority over decontamination and activated
charcoal is not indicated until the airway is secured by
TOXICOLOGY HANDBOOK
• Following excessive dermal exposure, wash the skin with soap
and water.
Antidotes
• None available.
• Excessive dermal exposure only warrants referral to hospital if
symptoms occur.
• Patients with objective evidence of organochlorine intoxication as
evidenced by gastrointestinal or neurological symptoms are
managed in a hospital location capable of managing seizures.
Those that develop features of major intoxication (recurrent
seizures or coma) require admission to the intensive care unit for
ongoing supportive care.
• Patients may be safely discharged once all symptoms resolve.
Follow-up is not necessary if asymptomatic.
HANDY TIPS
• The seizures associated with acute intoxication are usually rapid
in onset, short duration and controlled with benzodiazepines.
ERRNVPHGLFRVRUJ
• Ventricular dysrhythmias associated with organochlorines are rare
and may respond to IV beta-blockers (e.g. metoprolol or
propranolol).
PITFALL
• Failure to recognise the onset of acute toxicity, manifested by
vomiting, agitation or perioral paraesthesia.
CONTROVERSY
• The chronic subclinical effect of the organochlorines, including
their carcinogenic potential.
Presentations
SPECIFIC TOXINS
Most organochlorines are solid at room temperature and dissolved in hydrocarbon for
ease of application.
Industrial formulations
Aldrin, Chlordane, Dichlorodiphenyltrichloroethane (DDT), Dieldrin, Endosulfan, Endrin,
Ethylan, Heptachlor, Hexachlorobenzene, Isobenzan, Lindane, Methoxychlor
Medical formulations
Lindane 1% shampoo or lotion
References
322 Aks SE, Krantz A, Hryhorczuk DO et al. Acute accidental lindane ingestion in toddlers.
Annals of Emergency Medicine 1995; 26(5):647–651.
32
Baselt R. Disposition of Toxic Chemicals and Drugs in Man. 5th edn. Foster City,
2

TOXICOLOGY HANDBOOK
CDC. Unintentional topical lindane ingestions – United States, 1998–2003. MMWR

Morbidity Mortality Weekly Report 2005; 54(21):533–535.
3.59 ORGANOPHOSPHORUS AGENTS

(organophosphates and carbamates)
Organophosphates: Chlorpyrifos, Coumaphos, Diazinon, Dichlorvos,
Dimethoate, Fenthion, Malathion, Parathion, Trichlorfon Carbamates:
Aldicarb, Carbendazim, Carbendazole, Carbazine, Propoxur Chemical
nerve agents: Sarin (GB), Soman (GD), Tabun (GA), VX
Deliberate self-poisoning with organophosphate and carbamate
insecticides is responsible for more than 100 000 deaths worldwide each
year. Although agent-dependent variations in clinical features occur,
these agents generally cause death by respiratory failure. Attention to
the principles of resuscitation and supportive care, together with use of
antidotes, is essential to achieve a good outcome.
RISK ASSESSMENT
• Deliberate self-poisoning by ingestion of organophosphates
almost always produces life-threatening toxicity.
• Deliberate self-poisoning by ingestion of carbamates produces
similar serious toxicity, but is usually of shorter duration and less
likely to be life threatening.
• Onset of clinical manifestations of poisoning may be delayed up
to 12 hours with some agents.
ERRNVPHGLFRVRUJ
• Inadvertent or accidental occupational dermal or inhalational
exposure can cause toxicity but is rarely life threatening.
• Significant secondary poisoning of staff (nosocomial poisoning)
does not occur.
• Children: any ingestion of organophosphates or carbamates is
potentially lethal.
Toxic mechanism
Organophosphates inhibit acetylcholinesterase (AChE) enzymes, and increase
acetylcholine (ACh) concentration at both muscarinic and nicotinic cholinergic receptors.
Clinical features are secondary to the widespread effects of increased ACh at CNS,
autonomic (parasympathetic and sympathetic) and skeletal muscle neuromuscular
synapses. Irreversible loss of an alkyl side chain and permanent binding of the
organophosphate (‘ageing’) prevents reactivation of AChE by the antidote, pralidoxime.
SPECIFIC TOXINS
The time taken for ageing to occur depends on the individual agent. Ageing does not
occur with carbamates. Organophosphates and carbamates are frequently formulated
with hydrocarbon solvents (e.g. xylene). Inhalation of solvent fumes can produce headache
and dizziness but this does not indicate organophosphate poisoning. The insecticides
themselves have very low vapour pressures and are only inhaled when aerosolised.
Toxicokinetics
These agents are well absorbed after ingestion. Dermal and inhalational represent
important routes following occupational exposure. Agents generally have large volumes
of distribution and some accumulation in lipid stores. Carbamates are distributed less to
the CNS. Lipid solubility is a feature of the thioates. Thioates (e.g. malathion, parathion, 323
fenthion) act as indirect agents; they require metabolism to their active forms.
Metabolism of organophosphate compounds is primarily hydrolysis by serum HDL-bound
esterase enzymes (paraoxonases). Others undergo hepatic microsomal (cytochrome
TOXICOLOGY HANDBOOK
P450) metabolism with excretion of inactive metabolites in the urine. Most carbamates
are metabolised in the liver by oxidation, hydrolysis or conjugation and then excreted in
the urine.
CLINICAL FEATURES
• Timing of symptom onset depends on the agent, dose and route
of exposure. Symptoms may occur within minutes following
ingestion of some agents (e.g. dimethoate, chlorpyrifos) or be
delayed by many hours.
• The constellation and progression of symptoms is variable and
either muscarinic or nicotinic features can predominate.
• Dimethoate intoxication is characterised by the early onset of
coma, cardiovascular collapse and death within 24 hours.
• Chlorpyrifos is associated with early cholinergic symptoms.
• Fenthion is associated with few early symptoms but the late onset
(up to 2 days) of paralysis.
• Typical clinical syndromes include:
Acute intoxication
— Muscarinic effects
– Diarrhoea, urination, miosis, bronchorrhoea,
bronchospasm, emesis, lacrimation, salivation
(‘DUMBBELS’ mnemonic)
– Bradycardia and hypotension
— Nicotinic effects
– Fasciculation, tremor, weakness, respiratory muscle
paralysis
– Tachycardia and hypertension
ERRNVPHGLFRVRUJ
– Note: tachycardia is frequently present due to hypoxia
and hypotension
– Agitation, coma, seizures
— Respiratory
– Chemical pneumonitis if hydrocarbon solvent aspirated
– For further detail on the cholinergic syndrome, see
Chapter 2.10: Cholinergic syndrome
Intermediate syndrome
— Delayed onset of paralysis occurring 2–4 days after apparent
recovery from initial muscarinic symptoms. This syndrome is
associated with particular agents (e.g. fenthion, diazinon,
malathion) but the pathophysiology is not well understood.
SPECIFIC TOXINS
Hypotheses include prolonged motor end-plate stimulation,

delayed redistribution from lipid stores and inadequate initial
pralidoxime dosing
Delayed neurotoxicity
— Organophosphate-induced delayed neuropathy (OPIDN) is rare
and occurs 1–5 weeks post acute exposure to particular
agents (e.g. fenthion, chlorpyrifos, parathion). It is an ascending
sensorimotor polyneuropathy thought to be secondary to
324 ageing of axonal neuropathy target esterase (NTE)
32
4
Chronic organophosphate-induced neuropsychiatric disorder

— Long-term neuropsychiatric disorder, which may occur
TOXICOLOGY HANDBOOK
following acute intoxication or chronic low-level exposure.
INVESTIGATIONS
• Red cell and plasma (butyryl-, pseudo-) cholinesterase activities
— The diagnosis and management of acute anticholinesterase
poisoning is primarily clinical, but measures of cholinesterase
activity can be useful in making a definitive diagnosis and to
monitor therapy.
— Access to these assays can be difficult and samples must be
processed promptly due to ongoing in vitro reactions.
— Significant clinical features generally occur at levels <25% of
normal activity.
— Plasma cholinesterase activity is a sensitive biomarker of
anticholinesterase exposure, but has no relation to the severity
of the poisoning. It falls more rapidly and recovers more
quickly (4–6 weeks) than red cell cholinesterase activity. Once
it starts to increase, it suggests that the plasma concentration
of the anticholinesterase compound is negligible.
— Red cell cholinesterase activity correlates better with severity
of anticholinesterase poisoning and takes longer to recover
(120 days). It returns to normal following successful oxime
therapy and is used to monitor progress when oximes are
withdrawn.
ERRNVPHGLFRVRUJ
— The mixed cholinesterase test has been advocated as a
method to assess adequacy of therapy. It has not been
validated. Patient and control serum are mixed in a 50 : 50
ratio. A plasma cholinesterase activity of the mixed sample
that is less than the mean of the two unmixed samples
suggests the patient’s plasma contains unbound
organophosphate and increased oxime administration is
indicated.
MANAGEMENT
• Place the patient in an area equipped for cardiorespiratory
monitoring and resuscitation, ensuring that it is well ventilated to
SPECIFIC TOXINS
minimise complications of hydrocarbon vapour inhalation.
include:
— Coma (see Chapter 2.4: Coma)
— Hypotension (see Chapter 2.5: Hypotension)
— Seizures (see Chapter 2.6: Seizures)
— Respiratory failure.
• Resuscitation must not be delayed by external decontamination
procedures, which should proceed simultaneously. Staff should
use universal precautions. More sophisticated personal protective 325
equipment is not indicated.
• If there is miosis, excessive sweating, poor air entry, wheeze,
cough, bradycardia or hypotension, start escalating doses of
TOXICOLOGY HANDBOOK
atropine (see below and Chapter 4.1: Atropine).
• Control agitation with carefully titrated doses of benzodiazepines.
• Institute general supportive care, as outlined in Chapter 1.4:
Decontamination
• Remove clothes and wash skin with soap and water. Clothing
should be bagged.
• Activated charcoal confers no benefit and is not indicated.
Antidotes
• Atropine
— Atropine in escalating doses is indicated to control significant
clinical features of cholinergic excess: excessive sweating,
reduced breath sounds, wheeze, cough, bradycardia or
hypotension.
— Administer 1.2 mg (50 microgram/kg in children) IV and
double the dose every 5 minutes until there is resolution of
bradycardia, drying of secretions and good air entry. Large
doses may be required. Continuing administration as repeat
bolus doses or an infusion is frequently required.
— Note: Atropine has no effect on the neuromuscular junction
and muscle weakness.
— For more information on indications, administration and
therapeutic end points see Chapter 4.1: Atropine.
ERRNVPHGLFRVRUJ
• Pralidoxime
— Pralidoxime may reverse neuromuscular blockade by
reactivating inhibited AChE before ageing occurs. However,
the clinical utility of pralidoxime is now controversial (see
Controversies below).
— Give 2 g IV then continue an infusion of 0.5 g/hour for at least
24 hours.
— Pralidoxime is not necessary in carbamate intoxication.
— For more information on indications, administration and
therapeutic end points see Chapter 4.23: Pralidoxime.

• Any adult patient who has deliberately self-poisoned with an
organophosphate or carbamate insecticide is admitted for a
SPECIFIC TOXINS
minimum of 12 hours close observation. Discharge does not

occur at night.
• Any child suspected of ingesting an organophosphate or
carbamate insecticide is admitted for a minimum of 12 hours
close observation. Discharge does not occur at night.
• Patients with objective evidence of organophosphate or
carbamate intoxication requiring antidote administration are
admitted to an area with resources and staff available to detect
326 respiratory and neuromuscular complications and monitor
response to therapy.
32
•
6
Patients are observed for 24 hours after the cessation of oxime

therapy.
TOXICOLOGY HANDBOOK
• Follow-up is arranged to detect intermediate and delayed

syndromes.
• Adult patients with potential occupational exposure do not require
referral to hospital unless they develop significant symptoms.
PITFALLS
• Failure to appreciate the risk of life-threatening poisoning in the
patient who presents asymptomatic.
• Failure to recognise the cholinergic syndrome.
• Excessive concern about risks of nosocomial poisoning. This is
not documented following exposure to the organophosphate
poisoned patient and unwarranted concerns should not
compromise patient care. Universal precautions and management
in a well-ventilated room to reduce the strong smell of the
hydrocarbon solvent are appropriate.
CONTROVERSIES
• The value of pralidoxime in improving clinical outcome from
organophosphate poisoning is disputed. Although pralidoxime has
been shown to reactivate red cell acetylcholinesterase in some
organophosphate poisoned patients, it has not been shown to
improve survival or reduce the need for intubation and, indeed, in
some trials is associated with poorer clinical outcomes.
• The value of serum alkalinisation in organophosphate poisoning.
• The value of non-depolarising muscle relaxants. Early evidence
suggests they may reduce delayed neuromuscular effects by
protecting the neuromuscular junction.
ERRNVPHGLFRVRUJ
Presentations
These agents may be in both solid and liquid forms. They are
frequently formulated with organic solvents such as toluene, in
varying concentrations.
References
Buckley NA, Eddleston M, Li Y et al. Oximes for acute organophosphate poisoning.
Cochrane Database of Systematic Reviews 2011; 2.
Eddleston M, Eyer P, Worek F et al. Differences between organophosphorus
insecticides in human self-poisoning: a prospective cohort study. Lancet 2005;
366:1452–1459.
Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide
poisoning: a randomised controlled trial. PLoS Medicine 2009; 6(6):e1000104.
Published online 30 June 2009.
SPECIFIC TOXINS
Little M, Murray L. Consensus statement: risk of nosocomial organophosphate
poisoning in emergency departments. Emergency Medicine Australasia 2004;
16:456–458.
Pawar KS, Bholte RR, Pillay CP et al. Continuous pralidoxime infusion versus repeated
bolus injection to treat organophosphorus pesticide poisoning: a randomized
Roberts DM, Aaron CK. Management of acute organophosphorus pesticide poisoning.
British Medical Journal 2007; 334(7594):629–634.
327
3.60 PARACETAMOL: ACUTE OVERDOSE
TOXICOLOGY HANDBOOK
Acetaminophen; N-acetyl-p-aminophenol (APAP)
See also Chapter 3.62: Paracetamol: Repeated supratherapeutic
ingestion, Chapter 3.61: Paracetamol: Modified-release preparations.
This chapter refers to a single or staggered ingestion of excessive
immediate-release paracetamol over 8 hours or less. Provided that the
time of ingestion is well-defined, risk assessment and the decision to
treat (or not) with the antidote, N-acetylcysteine (NAC), is straightforward
and guided by a serum paracetamol level plotted on a nomogram. Where
the nomogram cannot be utilised, the decision to treat is based on
serum paracetamol and hepatic transaminase levels.
RISK ASSESSMENT
• Life-threatening hepatotoxicity is uncommon and fatalities are
rare.
• The threshold dose for paracetamol-induced hepatic injury in
adults is extremely variable but usually considered to be >10 g or
>200 mg/kg.
• The risk of hepatic injury following a single acute ingestion
without NAC is predicted by plotting a serum paracetamol level
taken 4–15 hours later on the Prescott or Rumack–Matthew
nomogram (see Figure 3.60.1 for a modified version of this
nomogram). The probability of hepatotoxicity (defined as peak
AST or ALT >1000 IU/L) is:
— 1–2% if 4-hour level is <1320 micromol/L (200 mg/L)
— 30% if 4-hour level is 1320–1980 micromol/L (200–300 mg/L)
— 90% if 4-hour level is >1980 micromol/L (300 mg/L).
ERRNVPHGLFRVRUJ
32
8
328
TOXICOLOGY HANDBOOK SPECIFIC TOXINS
FIGURE 3.60.1 Paracetamol treatment nomogram recommended for use in Australia and New Zealand
Blood
paracetamol
concentration Blood
paracetamol
(µmol/L) concentration
(mg/L)
ERRNVPHGLFRVRUJ
Time (hours)
Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008; 188:296–301.
• The risk of hepatic injury with NAC therapy is determined primarily
by time from overdose to commencement of NAC.
— Survival is 100% where NAC is commenced within 8 hours of
ingestion (a small percentage of patients develop minor
elevation of hepatic transaminases).
— Benefit is reduced where NAC is commenced 8–24 hours
following ingestion.
— Benefit is not established if NAC is commenced >24 hours
following ingestion except in fulminant hepatic failure, where
IV NAC decreases cerebral oedema, inotrope requirements
and mortality.
• Risk assessment is problematic if the time of ingestion is
unknown or staggered. The nomogram may still be able to be
applied using time-anchoring strategies (see Handy Tips below).
SPECIFIC TOXINS
• Patients who present >8 hours after overdose with elevated
hepatic transaminases are assumed to have early paracetamol-
induced hepatotoxicity.
• The patient who presents >24 hours following an overdose and
has normal hepatic transaminases and no detectable paracetamol
has little risk of developing clinically significant hepatotoxicity.
• For massive ingestions (>500 mg/kg) standard NAC administration
protocols may be insufficient to prevent hepatotoxicity.
329
• Children: there are no reports of death following single acute
non-intentional paracetamol exposure in children under 8 years of
age. Ingestion of <200 mg/kg as a single dose or over a period of
TOXICOLOGY HANDBOOK
<8 hours does not warrant decontamination, referral to hospital,
serum paracetamol level, liver function tests, antidote treatment or
follow-up.
Toxic mechanism
Elevated production of N-acetylparabenzoquinone imine (NAPQI) following paracetamol
overdose leads to depletion of hepatic glutathione stores. Once glutathione levels reach
a critical threshold (30% of normal), NAPQI starts binding to other proteins, causing
hepatocyte injury. The hallmark of paracetamol-induced hepatic injury is centrilobular
necrosis.
Toxicokinetics
Paracetamol is well absorbed from the small intestine following oral administration; peak
levels usually occur within 1–2 hours for standard tablet or capsule preparations and
within 30 minutes for liquid preparations. The volume of distribution is 0.9 L/kg. Ninety
per cent of paracetamol undergoes hepatic glucuronidation or sulfation. These
conjugates are excreted in the urine. Most of the remainder is oxidised by the
cytochrome P450 system to form NAPQI, a potentially toxic intermediate. Under normal
circumstances, NAPQI is immediately bound by intracellular glutathione and eliminated in
the urine as mercapturic adducts.
CLINICAL FEATURES
• Apart from early gastrointestinal upset, the clinical features are
those of progressive hepatic injury, which develops in a minority
of patients.
• Transient coma and early metabolic acidosis are rare, but
reported following massive paracetamol ingestion.
• The four classically described clinical phases of paracetamol
hepatotoxicity are described in Table 3.60.1.
ERRNVPHGLFRVRUJ
TABLE 3.60.1 Clinical phases of acute paracetamol overdose
Phase 1 Patients are frequently asymptomatic but may

(<24 hours) have nausea and vomiting
Phase 2 Right upper quadrant tenderness is common.

(1–3 days) Hepatic transaminases (ALT/AST) rise
rapidly to a peak at 48–72 hours and may
reach 15 000–20 000 IU/L. Hepatotoxicity is
defined as an ALT or AST >1000 IU/L. In
survivors, ALT/AST rapidly return to
baseline. Prothrombin time and INR are at
their most abnormal within hours of peak
SPECIFIC TOXINS
AST/ALT. Hyperbilirubinaemia also occurs

and renal function may be impaired
Phase 3 In very severe cases, hepatotoxicity progresses

(3–4 days) to fulminant hepatic failure with
coagulopathy, jaundice, encephalopathy
and multiple organ failure.
Death may occur in this phase. Non-survivors
demonstrate metabolic acidosis with
330 elevated lactate despite resuscitation, renal
failure (serum creatinine >300 micromol/L),
33
0
worsening coagulopathy (PT >100 seconds)

and encephalopathy
TOXICOLOGY HANDBOOK
Phase 4 Recovery phase during which hepatic structure

(4 days–2 weeks) and function return to normal
INVESTIGATIONS
• 12-lead ECG and BGL. An untimed ‘screening’ paracetamol level
is not useful following deliberate self-poisoning with paracetamol
and should be replaced by a specific timed level (see below).
• A recommended approach to initial investigations is outlined in
Table 3.60.2.
• Serum paracetamol
— If the time of ingestion is known, a timed paracetamol level is
taken at 4 or more hours to establish risk of hepatotoxicity
and need for treatment.
— If NAC is commenced within 8 hours of a single acute
ingestion, the first serum paracetamol level is the only
investigation required.
— Following massive (>500 mg/kg) overdose, the paracetamol
level is repeated towards the end of the NAC infusion. A
detectable paracetamol concentration is an indication to
continue infusion of NAC.
• Hepatic transaminases
— If NAC is commenced later than 8 hours, baseline and serial
hepatic transaminase levels are also taken to detect and
ERRNVPHGLFRVRUJ
TABLE 3.60.2 Recommended initial investigations according to time
from paracetamol ingestion to NAC treatment
Time after paracetamol ingestion
Test <8 hours 8–24 hours >24 hours
Serum paracetamol At 4 hours or At presentation At presentation

as soon
thereafter
as possible
Transaminases Not indicated At presentation At presentation

(ALT/AST) and at end
SPECIFIC TOXINS
of 20-hour
NAC infusion
INR/prothrombin time Not indicated Not indicated At presentation
Creatinine and urea Not indicated Not indicated At presentation
Glucose Not indicated Not indicated At presentation
Arterial blood gas Not indicated Not indicated At presentation 331

Adapted from Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia
2008; 188:296–301.
TOXICOLOGY HANDBOOK
monitor hepatic injury. The magnitude of elevation of ALT or
AST is not, however, linked to outcome.
• Coagulation studies
— Elevation of the INR is an important marker of hepatic injury.
• Platelet count, renal function and acid–base status
— Useful to assess and monitor clinical status and prognosis of
established hepatotoxicity.
MANAGEMENT
• Resuscitation is required only in the rare instances of coma due
to massive acute ingestion, and delayed presentation with
established hepatic failure. In such cases, urgent attention to
airway, breathing and circulation, plus correction of
hypoglycaemia are required.
• General supportive care and monitoring measures are indicated,
as outlined in Chapter 1.4: Supportive care and monitoring.
• Patients with rising hepatic aminotransferase levels and INR >2.5
should have 4-hourly recording of vital signs and bedside serum
glucose, and close monitoring of fluid balance.
Decontamination
• Oral activated charcoal is not life saving.
— It may be offered to the cooperative adult who presents within
the first hour following overdose, in which case it may
sufficiently reduce the 4-hour paracetamol level to such a
degree that NAC will be unnecessary.
ERRNVPHGLFRVRUJ
— It is never justified following acute ingestion of paracetamol by
small children.
Antidotes
• Intravenous NAC is indicated in all patients in whom the risk
assessment suggests potential for poor outcome and in patients
who present late with clinical or biochemical evidence of hepatic
injury.
• Presentation <8 hours following a defined time of ingestion:
— The decision to initiate NAC is deferred until the result of a
paracetamol level taken at 4 hours or later is plotted on the
SPECIFIC TOXINS
nomogram.
• Presentation 8–24 hours following a defined time of ingestion:
— NAC is initiated immediately and continued or ceased once a
paracetamol level is available and plotted on the nomogram.
• Unknown time of ingestion:
— If paracetamol is detectable, but the time of ingestion is
unknown (this commonly occurs where coma or delirium
prevents history taking), NAC is commenced immediately. It
may be ceased later when history is available or if hepatic
332 transaminases are found to be normal at the end of the
33
20-hour NAC infusion.

2
• Presentation >24 hours post ingestion:

— NAC is only indicated if paracetamol is detectable or hepatic
TOXICOLOGY HANDBOOK
transaminases are elevated. It is continued until hepatic

transaminases are falling and the patient is improving
clinically. NAC may be commenced pending biochemical
assessment in the patient with nausea, vomiting, abdominal
pain or encephalopathy.
• A management flow chart for acute paracetamol exposure with
known time of ingestion is shown in Figure 3.60.2.
• Note: See Chapter 4.17: N-acetylcysteine for full details on
dosing and administration of NAC.

• Patients in whom NAC is commenced within 8 hours of ingestion
do not require further investigation or follow-up (except in the
case of ingestion of >500 mg/kg when a repeat paracetamol level
is indicated at the end of infusion). They are fit for medical
discharge at the termination of the 20-hour infusion.
• Patients in whom NAC is commenced later than 8 hours following
ingestion (or unknown time of ingestion) have hepatic
transaminases tested at baseline and at the end of the 20-hour
infusion. If they are normal at that time, NAC is ceased. If
abnormal, NAC continues at 100 mg/kg/16 hours and hepatic
transaminases are tested every 12–24 hours until falling. If hepatic
transaminases exceed 1000 IU/L, serial testing also includes INR,
renal function and platelet count.
• In uncommon cases, rising INR and hepatic transaminases
herald fulminant hepatic failure and the need to transfer to
a liver transplant service. Arrangements for transfer to such
ERRNVPHGLFRVRUJ
FIGURE 3.60.2 Management flow chart for acute paracetamol
exposure with known time of ingestion
<1 hour 1–8 hours >8 hours
Activated Measure serum Commence

charcoal* paracetamol NAC infusion
level within 4–8
hours of
ingestion Measure serum
paracetamol
level & ALT
SPECIFIC TOXINS
UNDER Plot serum Plot serum UNDER
nomogram paracetamol paracetamol treatment line
treatment line level on level on or >24 hrs post
nomogram nomogram OD
Medical
treatment not OVER OVER ALT normal
required nomogram nomogram
treatment line treatment line
333
TOXICOLOGY HANDBOOK
Commence Continue NAC
no yes
NAC infusion infusion
No further Measure ALT at STOP NAC

investigation end of NAC
required infusion
No further
treatment
yes ALT normal required
Continue NAC
no
and monitor
*Cooperative adult patients who have potentially ingested greater than 10 g or

200 mg/kg, whichever is less
Source: Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008;
188:296–301.
ERRNVPHGLFRVRUJ
a facility should occur if any of the following high-risk criteria
develop:
— INR >3.0 at 48 hours or >4.5 at any time
— Oliguria or creatinine >200 micromol/L
— Acidosis with pH <7.3 after resuscitation
— Systolic hypotension with BP <80 mmHg
— Hypoglycaemia
— Severe thrombocytopenia
— Encephalopathy of any degree.
HANDY TIPS
• Time-anchoring strategies may be used to determine risk of
hepatotoxicity and need for NAC where time of ingestion is
SPECIFIC TOXINS
uncertain. Plot the measured paracetamol level on the nomogram

line and determine the time before which the ingestion must have
taken place to be of concern. It should then be determined whether
it is possible for the overdose to have occurred before that time.
• If multiple ingestions have occurred over a few hours (e.g. at 1
pm, 3 pm and 4 pm) a worst-case scenario may be constructed.
A serum paracetamol level may be drawn and plotted on the
nomogram, assuming that the entire dose was taken at the
earliest time. If it is above the line, NAC is commenced.
334 • Paracetamol poisoning should be considered in the differential
33
diagnosis of metabolic acidosis and in any case with AST/ALT

4
> 1000 IU/L.
TOXICOLOGY HANDBOOK
PITFALLS
• Failure to commence NAC immediately in the patient who
presents more than 8 hours following a paracetamol overdose.
• NAC dosing errors (see Chapter 4.17: N-acetylcysteine for
advice on safe charting of NAC infusions).
• Failure to check paracetamol units. Different units are used to
report paracetamol levels (micromol/L, mol/L and mg/L). Incorrect
plotting of level may lead to a potentially lethal error.
CONTROVERSIES
• Choice of nomogram. A variety of nomograms are used around
the world. The Prescott nomogram uses a line extending from
200 mg/L (1320 micromol/L) at 4 hours to 30 mg/L at 15 hours
using a semi-logarithmic scale. The Rumack–Matthew nomogram
uses a line extending from 150 mg/L at 4 hours to 37.5 mg/L at
12 hours using a semi-logarithmic scale. The line is extrapolated
to 6 mg/L at 24 hours. The United Kingdom’s Medicines and
Healthcare products Regulatory Agency (MHRA) recently lowered
the treatment threshold to a line extending from 100 mg/L (662
micromol/L) at 4 hours to 15 mg/L (100 micromol/L) at 15 hours.
Appropriate use of the available nomogram by ensuring accurate
time of ingestion, appropriate interpretation of units and early
NAC is far more important than which nomogram or nomogram
line is used.
• Although commonly done and clinically useful, extrapolation of the
treatment line from 15 to 24 hours has not been formally validated.
ERRNVPHGLFRVRUJ
• Various models have been developed in an attempt to define the
risk at presentation of subsequently developing hepatotoxicity or
fulminant hepatic failure.
• Risk factors for paracetamol-induced liver injury. Some authorities
hypothesise that chronic alcoholism (ingestion of >50 g/day),
prolonged fasting and use of particular medications (inducers of
cytochrome P450 2E1 and 3A4; isoniazid, rifampicin and
carbamazepine) are likely to increase the risk of hepatotoxicity.
• Antidotal treatment of massive (>500 mg/kg) paracetamol
overdose. It has been proposed that NAC infusion rates be
increased in this group of patients. At the very least, most
authorities recommend continuing the ‘third bag’ of NAC until
paracetamol is no longer detected in the serum.
SPECIFIC TOXINS
Presentations
Paracetamol 500 mg/metoclopramide Paracetamol 500 mg/pseudoephedrine
5 mg tablets (8, 10, 24) 30 mg tablets (24)
Paracetamol 325 mg/dextropropoxyphene Paracetamol 400 mg/pseudoephedrine
32.5 mg capsules (20) 30 mg tablets (10, 30, 50)
Paracetamol 325 mg/dextropropoxyphene Paracetamol 1000 mg/pseudoephedrine
32.5 mg tablets (20) 60 mg sachets (10)
Paracetamol 500 mg tablets (12, 24, 48, Paracetamol 500 mg/pseudoephedrine
50, 96, 100, 500) 30 mg/triprolidine 1.25 mg tablets (8,
Paracetamol 500 mg capsules (24, 48, 16, 20, 24) 335
96) Paracetamol 500 mg/pseudoephedrine
Paracetamol 500 mg caplets (10, 12, 20, 30 mg/codeine phosphate 9 mg
24) tablets (24, 30, 48, 60)
TOXICOLOGY HANDBOOK
Paracetamol 500 mg gel cap tablets (12, Paracetamol 500 mg/pseudoephedrine
24, 48) 30 mg/codeine phosphate 6 mg
Paracetamol 250 mg soluble tablets (12) tablets (16, 24, 32, 48)
Paracetamol 500 mg soluble tablets (20) Paracetamol 500 mg/pseudoephedrine
Paracetamol 500 mg gel tablets (12, 24) 30 mg/dextromethorphan 10 mg
Paracetamol 120 mg chewable tablets capsules (18, 24)
(24) Paracetamol 300 mg/pseudoephedrine
Paracetamol 160 mg chewable tablets 30 mg/dextromethorphan 10 mg
(24) capsules (18, 24)
Paracetamol 665 mg modified-release Paracetamol 300 mg/pseudoephedrine
tablets (96, 192) 30 mg/dextromethorphan 10 mg/
Paracetamol 665 mg extended-release doxylamine 6.25 mg capsules (6, 16,
tablets (18, 36) 20)
Paracetamol 1000 mg sachets (5, 10) Paracetamol 500 mg/chlorpheniramine
Paracetamol 500 mg sachets (10) 2 mg/dextromethorphan 10 mg
Paracetamol 125 mg suppositories (20) capsules (6)
Paracetamol 250 mg suppositories (20) Paracetamol 500 mg/pseudoephedrine
Paracetamol 500 mg suppositories (24) 30 mg/dextromethorphan 15 mg
Paracetamol 10 mg/1 mL vials (50 mL, tablets (18, 24, 36)
100 mL) Paracetamol 650 mg/pseudoephedrine
Paracetamol liquid 120 mg/5 mL (100 mL, 30 mg/dextromethorphan 15 mg/
200 mL) chlorpheniramine 4 mg sachets (10)
Paracetamol liquid 240 mg/5 mL (100 mL, Paracetamol 325 mg/pseudoephedrine
200 mL) 30 mg/dextromethorphan 15 mg
Paracetamol drops 100 mg/1 mL (20 mL) tablets (18, 24, 48)
Paracetamol 160 mg/pseudoephedrine Paracetamol 325 mg/dextromethorphan
15 mg/chlorpheniramine 1 mg per 15 mg/chlorpheniramine 2 mg tablets
5 mL liquid (100 mL, 200 mL) (6, 24)
Paracetamol 120 mg/pseudoephedrine Paracetamol 325 mg/pseudoephedrine
20 mg/dextromethorphan 7.5 mg per 30 mg/dextromethorphan 15 mg/
5 mL liquid (100 mL, 200 mL) chlorpheniramine 2 mg tablets (24)
ERRNVPHGLFRVRUJ
Paracetamol 500 mg/pseudoephedrine Paracetamol 450 mg/codeine phosphate
30 mg/chlorpheniramine 2 mg tablets 30 mg/doxylamine succinate 5 mg
(6, 12, 24, 30, 60) tablets (20)
Paracetamol 325 mg/pseudoephedrine Paracetamol 450 mg/orphenadrine citrate
30 mg/chlorpheniramine 2 mg tablets 35 mg tablets (100)
(10, 30, 50) Paracetamol 500 mg/codeine phosphate
Paracetamol 500 mg/pseudoephedrine 10 mg tablets (24, 48, 96)
30 mg/chlorpheniramine Paracetamol 500 mg/codeine phosphate
2 mg/codeine phosphate 8 mg tablets (12, 20, 24, 48, 50, 96,
9.5 mg (24) 100)
Paracetamol 500 mg/chlorpheniramine Paracetamol 500 mg/codeine phosphate
2 mg tablets (24) 30 mg tablets (20, 50)
Paracetamol 500 mg/doxylamine Paracetamol 500 mg/codeine phosphate
succinate 5.1 mg/codeine phosphate 9.6 mg caplets (12, 20, 24, 40, 48)
10 mg tablets (20) Paracetamol 500 mg/codeine phosphate
SPECIFIC TOXINS
Paracetamol 500 mg/doxylamine 15 mg caplets (12)

succinate 5.1 mg/codeine phosphate Paracetamol 500 mg/codeine phosphate
9.6 mg tablets (10, 20) 15 mg tablets (20, 50)
Paracetamol 500 mg/doxylamine Paracetamol liquid 120 mg/codeine
succinate 5 mg/codeine phosphate phosphate 5 mg per 5 mL (100,
8 mg tablets (20, 24) 200 mL)
Paracetamol 500 mg/doxylamine Paracetamol liquid 120 mg/codeine
succinate 2 mg/codeine phosphate phosphate 5 mg/promethazine 6.5 mg
10 mg capsules (20) per 5 mL (100 mL, 200 mL)
Paracetamol 450 mg/codeine phosphate Paracetamol 500 mg/caffeine 65 mg
336 9.75 mg/doxylamine succinate 5 mg caplets (12, 18, 24, 36, 48, 96)
tablets (20) Paracetamol 500 mg/ibuprofen 150 mg
33
6
Paracetamol 450 mg/codeine phosphate tablets (10, 16, 30)

9.75 mg/doxylamine succinate 5 mg Paracetamol 325 mg/tramadol 37.5 mg
TOXICOLOGY HANDBOOK
caplets (20) tablets (20, 50)
References
Daly FSS, Fountain JS, Murray L et al. Guidelines for the management of paracetamol
poisoning in Australia and New Zealand: explanation and elaboration. A consensus
statement from toxicologists consulting to the Australasian Poisons Information
Centres. Medical Journal of Australia 2008; 188:296–301.
Ferner RE, Dear JW. Management of paracetamol poisoning. British Medical Journal
2011; 342d2218.
O’Grady JG. Acute liver failure. Postgraduate Medical Journal 2005; 81:148–154.
Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. British Medical Journal 1979; 2:1097.
Rumack BH, Bateman DH. Acetaminophen and acetylcysteine dose and duration: past,
present and future. Clinical Toxicology 2012; 50:91–98.
Rumack BH, Matthew H. Acetaminophen poisoning and toxicity. Pediatrics 1975; 55:
871–876.
3.61 PARACETAMOL: MODIFIED-RELEASE

FORMULATIONS
Acetaminophen; N-acetyl-p-aminophenol (APAP)
See also Chapter 3.60: Paracetamol: Acute overdose, Chapter 3.62:
Paracetamol: Repeated supratherapeutic ingestion.
Modified-release paracetamol preparations are formulated to combine
immediate-release and delayed-release layers with increased total dose
per tablet. Delayed absorption and biphasic release means standard
ERRNVPHGLFRVRUJ
risk-assessment and treatment algorithms are not applicable and
prolonged biochemical assessment is required.
RISK ASSESSMENT
• Risk assessment is still being refined but is currently based on
dose and serial timed paracetamol concentrations.
• The threshold dose for paracetamol-induced hepatic injury in
adults is extremely variable but usually considered to be
>200 mg/kg (or >10 g).
• Two timed paracetamol levels at least 4 hours apart are plotted
on the paracetamol treatment nomogram (see Figure 3.60.1). If
either level is above the treatment line, there is judged to be a risk
of hepatotoxicity.
SPECIFIC TOXINS
• Children: ingestion of <200 mg/kg as a single dose or over a
period of <8 hours does not warrant decontamination, referral to
hospital, serum paracetamol levels, liver function tests, antidote
treatment or follow-up.
Toxic mechanism
See Chapter 3.60: Paracetamol: Acute overdose.
Toxicokinetics
Australian modified-release preparations consist of 665 mg of paracetamol, of which 337
69% is slow-release and 31% immediate-release, arranged in a bilayer tablet. This
formulation results in a prolonged absorption phase when compared to standard
formulations. Peak levels usually occur within 2–3 hours of ingestion but may be delayed
TOXICOLOGY HANDBOOK
up to 20 hours following overdose. Metabolism and elimination is as described in
Chapter 3.60: Paracetamol: Acute overdose.
CLINICAL FEATURES
Patients who develop toxicity following overdose manifest the clinical
phases of paracetamol toxicity as described in Table 3.60.1. Timely
treatment with N-acetylcysteine prevents or minimises subsequent
hepatotoxicity.
INVESTIGATIONS
• 12-lead ECG and BGL. An untimed ‘screening’ paracetamol level
is not useful following deliberate self-poisoning with modified-
release paracetamol and should be replaced by specific timed
levels (see below).
• Serum paracetamol
— A single timed paracetamol is insufficient to establish risk of
hepatoxicity following overdose of modified-release
preparations.
— If the time of ingestion is known, a timed paracetamol
level is taken at 4 or more hours and then repeated 4 hours
later if the initial level falls below the nomogram treatment
line.
— If NAC treatment is commenced, a paracetamol level is
repeated shortly before the termination of the NAC infusion to
determine the need to continue NAC.
ERRNVPHGLFRVRUJ
— If the time of ingestion is unknown, paracetamol levels are
taken on presentation and shortly before the termination
of NAC.
• Hepatic transaminases, coagulation studies, platelet count, renal
function and acid–base status may be useful to monitor clinical
status and prognosis of established hepatotoxicity as described in
Chapter 3.60: Paracetamol: Acute overdose.
MANAGEMENT
• Resuscitation is required only in the rare instances of coma due
to massive acute ingestion, and delayed presentation with
established hepatic failure. In such cases, urgent attention to
SPECIFIC TOXINS
airway, breathing and circulation, plus correction of

hypoglycaemia, are required.
• General supportive care and monitoring measures are
monitoring.
• Patients with rising hepatic aminotransferase levels and INR >2.5
338 Decontamination
33
• Oral activated charcoal is not life saving. It may be offered to

8
the co-operative patient who presents within 4 hours of

TOXICOLOGY HANDBOOK
ingestion.
Antidotes
• Intravenous NAC is indicated in all patients in whom the risk
assessment suggests potential for toxicity.
• Presentation within 24 hours of a defined time of ingestion
— Start NAC if history suggests ingestion of >200 mg/kg.
— Check paracetamol level at 4 hours post ingestion (or on
arrival if presentation greater than 4 hours post-ingestion) and
4 hours later if the initial level plot is below the nomogram
treatment line. If both levels are below the treatment line, NAC
may be discontinued.
— NAC is continued beyond the standard 20-hour infusion until
paracetamol is undetectable. (Recheck paracetamol level
shortly before the end of each infusion.)
• Unknown time of ingestion
— If paracetamol is detectable, but the time of ingestion
unknown (this commonly occurs where coma or delirium
prevents history taking), NAC is commenced immediately. It
may be ceased later when history is available or if there is no
detectable paracetamol and hepatic transaminases are normal
at the end of the 20-hour NAC infusion.
• Presentation >24 hours post ingestion
— NAC is only indicated if paracetamol is detectable or hepatic
transaminases are elevated. It is continued until paracetamol
ERRNVPHGLFRVRUJ
is undetectable, hepatic transaminases are stable or falling
and the patient is improving clinically. NAC may be
commenced pending biochemical assessment in the
patient with nausea, vomiting, abdominal pain or
encephalopathy.
• Note: See Chapter 4.17: N-acetylcysteine for full details on
dosing and administration of NAC.

• Because of the prolonged absorption and biphasic elimination
properties of the modified-release preparation, repeat serum
paracetamol concentrations must be performed to ensure
complete elimination prior to ceasing NAC.
• Patients in whom NAC is commenced later than 8 hours following
SPECIFIC TOXINS
ingestion (or unknown time of ingestion) or have evidence of
hepatic toxicity are admitted for further clinical and biochemical
monitoring as described in Chapter 3.60: Paracetamol: Acute
overdose.
HANDY TIP
• Consider the possibility of ingestion of modified-release
preparations of paracetamol where history suggests the ingestion
of multiples of 18 tablets or large packets containing 96 or 192 339
tablets.
TOXICOLOGY HANDBOOK
PITFALLS
• Failure to recognise ingestion of a modified-release formulation.
• Failure to commence NAC based on history of ingested dose in
early presenters. If NAC is withheld pending serial paracetamol
levels then the 8-hour ‘window’ period of maximal efficacy will
have elapsed.
• Failure to check paracetamol units. Different units are used to
report paracetamol levels (micromol/L, mol/L and mg/L). Incorrect
plotting of level may lead to a potentially lethal error.
CONTROVERSY
• Risk assessment based on paracetamol levels remains undefined
for modified-release preparations.
Presentations
Paracetamol controlled release tablets 665 mg (96, 192)
References
Chiew A, Day P, Salonikas C et al. The comparative pharmacokinetics of modified-
release and immediate-release paracetamol in a simulated overdose model.
Emergency Medicine Australasia 2010; 22:548–555.
Roberts DM, Buckley NA. Prolonged absorption and delayed peak paracetamol
concentration following poisoning with extended-release formulation. Medical
Journal of Australia 2008; 188:310–311.
ERRNVPHGLFRVRUJ
3.62 PARACETAMOL: REPEATED
SUPRATHERAPEUTIC INGESTION
Acetaminophen, N-acetyl-p-aminophenol (APAP)
See also Chapter 3.60: Paracetamol: Acute overdose, Chapter 3.61:
Paracetamol: Modified-release formulations.
Repeated supratherapeutic ingestion of paracetamol refers to staggered
dosing with therapeutic intent of >4 g/day in adults or >60 mg/kg/day in
children. In adults, it usually occurs in the context of self-medication for
acute pain or exacerbations of chronic pain. In children, it is usually a
therapeutic error. Repeated supratherapeutic ingestion is responsible for
SPECIFIC TOXINS
all deaths related to paracetamol in children less than 6 years of age and
up to 15% of those in adults. Standard nomograms do not apply. The
decision to treat is based on an estimation of dose in conjunction with
biochemical testing (serum paracetamol level and hepatic
aminotransferase levels).
RISK ASSESSMENT
• The Rumack–Matthew and Prescott nomograms are not useful.
340 • Risk assessment is based on dose history and biochemical
testing.
34
•
0
Adults (and children >6 years) are referred for biochemical risk
assessment if there is a history of ingestion of:
TOXICOLOGY HANDBOOK
— 10 g or >200 mg/kg (whichever is less) over a single 24-hour

period
or
— 6 g or 150 mg/kg/24 hours (whichever is less) for the
preceding 48 hours or longer.
• Patients who may be more susceptible to paracetamol
poisoning (e.g. alcoholism, isoniazid use or prolonged fasting)
are referred for biochemical risk assessment if they ingest >4 g
or 100 mg/kg/24 hours.
• Biochemical risk assessment is based on an untimed serum
paracetamol level and a hepatic transaminase level (ALT or AST)
at presentation:
— ALT or AST < 50 IU/L and paracetamol level <120 micromol/L
(<20 mg/L)
– Good prognosis
– No further investigation or treatment required, regardless
of reported dose
— ALT or AST >50 IU/L or paracetamol level >66 micromol/L
(>10 mg/L)
– Higher risk group
– Commence N-acetylcysteine (NAC) pending further
evaluation.
• Children: patients <6 years of age are referred for biochemical
risk assessment if there is a history of ingestion of:
— >200 mg/kg over a single 24-hour period
or
— >150 mg/kg/24 hours for the preceding 48 hours
ERRNVPHGLFRVRUJ
or
— >100 mg/kg/24 hours for the preceding 72 hours.
Toxic mechanism
Supratherapeutic doses of paracetamol can result in depletion of hepatic glutathione
stores. Once glutathione levels are depleted to below 30% of normal, the same toxicity
is observed as following acute paracetamol overdose.
Toxicokinetics
CLINICAL FEATURES
• Patients who go on to develop hepatic injury following
supratherapeutic paracetamol overdose encounter the same
SPECIFIC TOXINS
four clinical phases as for acute paracetamol poisoning (see
Table 3.60.1).
INVESTIGATIONS
• Serum paracetamol level and hepatic transaminase levels
(ALT/AST)
— Determine the risk of hepatotoxicity and requirement
for NAC.
• Liver function tests, urea and electrolytes, prothrombin time-INR, 341
acid–base status and blood glucose
— Monitor the clinical course of those patients with
hepatic injury (see Chapter 3.60: Paracetamol: Acute
TOXICOLOGY HANDBOOK
overdose).
MANAGEMENT
• Resuscitative efforts are only required in the rare instance where a
patient presents late in established hepatic failure with jaundice,
altered conscious state and hypoglycaemia. In such cases, urgent
attention to airway, breathing and circulation, plus correction of
hypoglycaemia and coagulopathy, are required.
• General supportive care and monitoring measures are
monitoring.
• Patients with worsening hepatic transaminase levels and INR >2.5
Decontamination
Antidotes
• N-acetylcysteine is indicated immediately if there are clinical
features of hepatitis and a history of repeated supratherapeutic
ingestion of paracetamol. Otherwise, it is commenced following
biochemical risk assessment (see above).
• Intravenous NAC is continued for at least 8 hours. Serum ALT or
AST measurement is repeated after that time. A rapid rise in
ERRNVPHGLFRVRUJ
hepatic transaminase levels is consistent with evolving
paracetamol hepatic injury and NAC is continued at 100 mg/kg
over 16 hours until the patient is clinically well and the ALT and
INR are falling. Falling or static serum AST/ALT values suggest
a resolving injury or alternative diagnosis and NAC may be
ceased.
• Note: For a detailed description of NAC and its administration see
Chapter 4.17: N-acetylcysteine.
• A management flow chart for repeated therapeutic ingestion of
paracetamol is shown in Figure 3.62.1.
SPECIFIC TOXINS
FIGURE 3.62.1 Management flow chart for repeated supratherapeutic

paracetamol ingestion
no
Does the patient meet the No further management
criteria for repeated required
supratherapeutic ingestion?
yes
Measure serum paracetamol

342 level and ALT
Adults and Children 6+ years
34
2
• At least 10 g or 200 mg/kg

(whichever is lower) over a
TOXICOLOGY HANDBOOK
ALT normal ANY OTHER

single 24-hour period
and serum RESULT
• At least 6 g or 150 mg/kg paracetamol
(whichever is lower) per 24-hour level
period for the preceding 48 hours <120 µmol/L Commence
• More than 4 g/day or (20 mg/L) NAC infusion
100 mg/kg (whichever is less)
in patients with pre-disposing
risk factors No further Repeat serum
Children treatment paracetamol
• 200 mg/kg or more over a required level and ALT at
single 24-hour period 8 hours
• 150 mg/kg or more per 24-hour
period for the preceding 48 hours
ALT normal or
• 100 mg/kg or more per 24-hour yes
static
period for the preceding 72 hours
no
Continue NAC and check ALT

at 12-hourly intervals.
Other parameters are
measured as indicated
Source: Daly FSS, Fountain JS, Murray L et al. Medical Journal of Australia 2008;
188:296–301.
ERRNVPHGLFRVRUJ
• Patients with clinical or biochemical evidence of hepatotoxicity
are admitted for NAC infusion and monitoring of liver function.
They may be discharged if they remain well once transaminase
levels are falling. In the absence of other hepatic pathology,
follow-up liver function tests are not indicated.
• Patients with fulminant hepatic failure require intensive care
admission and consideration for referral to a liver transplant
service (see Chapter 3.60: Paracetamol: Acute overdose for
precise referral criteria).
HANDY TIPS
• Enquire about analgesic use in all patients presenting with severe
SPECIFIC TOXINS
dental, back or pelvic pain.
• Minor elevations of ALT and AST (up to 300 IU/L) are common
and usually related to coexistent alcoholic or viral hepatitis. In the
absence of known previous values, NAC is started and continued
until it is demonstrated that hepatic aminotransferase levels are
not rising rapidly.
PITFALL
• Failure to identify cases of repeated supratherapeutic ingestion of 343
paracetamol.
CONTROVERSY
TOXICOLOGY HANDBOOK
• There are no published prospective studies of repeated
supratherapeutic ingestion of paracetamol in children and risk
assessment is controversial.
Presentations
References
Daly FSS, O’Malley GF, Heard K et al. Prospective evaluation of repeated
supratherapeutic acetaminophen (paracetamol) ingestion. Annals of Emergency
Medicine 2004; 44(4):393–398.
Dart RC, Erdman AR, Olson KR et al. Acetaminophen poisoning: an evidence-based
consensus guideline for out-of-hospital management. Clinical Toxicology 2006;
44:1–18.
3.63 PARAQUAT
Paraquat is a widely used herbicide that is potentially lethal following
ingestion of as little as a mouthful. If the dose is insufficient to cause
fulminating multi-organ failure and death, severe gastrointestinal
corrosive injury and rapid onset of pulmonary fibrosis are common.
Immediate decontamination and avoidance of supplemental oxygen
therapy are the mainstays of treatment.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Gastrointestinal corrosive injury is virtually universal after exposure
to paraquat.
• Survival after acute paraquat poisoning is related to dose (see
Table 3.63.1) and this in turn is strongly influenced by the
circumstances of poisoning (intentional versus accidental) and the
formulation ingested.
— Deliberate self-poisoning with concentrated formulations (20%
solution) is almost invariably fatal.
— Accidental ingestions have better survival rates. A mouthful
may cause toxicity but a taste or splash is unlikely to cause
problems.
SPECIFIC TOXINS
TABLE 3.63.1 Dose-related risk assessment: Paraquat
Dose Effect
<30 mg/kg Mild-to-moderate gastrointestinal effects

<0.15 mL/kg of 20% with full recovery expected
solution
<10 mL of 20% solution
344 in a 70-kg patient
34
4
30–150 mg/kg Significant gastrointestinal corrosive

0.15–0.75 mL/kg of injury followed by multiple organ
TOXICOLOGY HANDBOOK
20% solution failure (including renal and hepatic

10–50 mL of 20% injury) over 2–6 days, then pulmonary
solution in a 70-kg fibrosis several days post ingestion
patient Mortality very high (>50%)
>150 mg/kg Fulminant multiple organ failure and

>0.75 mL/kg of 20% alveolitis resulting in progressive
solution refractory hypoxia, metabolic
>50 mL of 20% solution acidosis, renal and hepatic injury and
in a 70-kg patient cardiovascular collapse
Mortality universal with death occurring
within 12 hours–7 days
• Inhalational exposures do not cause significant intoxication.

• Dermal exposure may cause toxicity if there is prolonged
exposure or exposure to broken skin.
• Risk assessment can be refined using urinary and serum paraquat
assays (see below).
• Children: ingestion of a teaspoonful (5 mL) may be fatal.
Toxic mechanism
Paraquat is a water-soluble para-substituted quaternary bipyridyl cation herbicide. It is
a caustic agent specifically transported into pneumocytes, where it causes superoxide
production and depletes superoxide dismutase and NADPH. Oxygen free radicals
cause lipid peroxidation, further free radical production and damage to cell membrane
integrity.
ERRNVPHGLFRVRUJ
Toxicokinetics
Absorption is rapid but incomplete. Bioavailability increases with dose and kinetics
become non-linear. Peak blood levels occur within 2–4 hours. Oral absorption is further
reduced by the presence of food in the stomach. Inhalational and dermal absorption via
intact skin are minimal. Prolonged exposure to concentrated solutions, or contact on
broken skin, may rarely result in systemic absorption. Distribution is rapid to highly
vascular tissues such as kidney, liver, heart, muscle and lungs. Paraquat is not
metabolised and is predominantly excreted by the kidneys. Biliary excretion is minor.
CLINICAL FEATURES
• Patients may initially appear well but complain of oral burns.
• Central tongue ulceration (‘paraquat tongue’) and gastrointestinal
symptoms are universal. Corrosive injury may be severe.
Oesophageal perforation and mediastinitis are reported.
SPECIFIC TOXINS
• Following large ingestions, multiple organ effects become
apparent within hours. Tachycardia and tachypnoea accompany
metabolic acidosis with elevated lactate. Cardiovascular collapse
and multi-system organ failure may lead to death within 24 hours
in severe cases.
• Patients with moderate ingestion may not develop systemic
toxicity during the first 48 hours but then develop acute renal
failure and progressive pulmonary injury characterised by early
alveolitis and secondary pulmonary fibrosis. The initial symptoms
are of increasing dyspnoea and hypoxia, which progresses until 345
death occurs within days to weeks. The renal injury resolves in
survivors.
TOXICOLOGY HANDBOOK
TABLE 3.63.2 Clinical progression: Paraquat
Time Effect
Immediate Vomiting and symptoms of gastrointestinal injury
Hours Corrosive injury to lips and oral cavity. Metabolic

acidosis develops early in large ingestions
<48 hours Progressive acidosis, cardiovascular instability,

renal failure, hepatic injury and progressive
hypoxaemia in large ingestions
>48 hours Progressive pulmonary injury with rapid

development of pulmonary fibrosis
INVESTIGATIONS
• Regular oxygen saturations
— Detect developing hypoxia and determine oxygen
requirement.
• Serial pulmonary function testing
— Detect developing alveolitis and pulmonary fibrosis.
ERRNVPHGLFRVRUJ
• Acid–base status, lactate, FBC, EUC, LFT
— Detect signs of multi-organ failure.
— Detect development and progress of acidosis and response
to treatment.
— Lactate >4.4 mmol/L is associated with fatal outcome.
• Chest X-ray
— Detect fibrosis and aspiration.
• Urinary paraquat
— The qualitative (dithionite) colorimetric spot test can be
performed by most laboratories on urine, gastric fluids or
dialysate.
— It is a reliable test for the presence of paraquat if performed
within 12 hours of ingestion and may remain positive for
several days following large ingestions.
SPECIFIC TOXINS
— Sodium dithionite reduces paraquat; a positive test is based

on reduction to a blue cation. The reaction occurs within
1 minute.
— A positive test demonstrates paraquat has been absorbed,
but does not indicate prognosis.
• Serum paraquat levels
— Not readily available within a clinically useful time frame but
invaluable in defining prognosis (see Figure 3.63.1).
346 — Ideally, samples should be collected 4–24 hours after
exposure.
34
6
TOXICOLOGY HANDBOOK
FIGURE 3.63.1 Paraquat survival nomogram
5.5
Plasma levels of paraquat (microgram/mL)
5.0
4.0
Percentages denote
3.0
the Probability of Survival
2.0
1.0
0
0 4 8 12 16 20 24 28
Hours after swallowing
Adapted from Hart TB, Nevitt A, Whitehead A. A new statistical approach to the
prognostic significance of plasma paraquat concentrations. Lancet 1984;
2(8413):1222–1223.
ERRNVPHGLFRVRUJ
MANAGEMENT
• Paraquat intoxication is a time-critical emergency.
• This is the only poisoning in which decontamination takes priority
over resuscitation or transport to hospital and ideally
decontamination occurs at the scene (see below).
• Patients are managed in an area equipped for cardiorespiratory
• Patients who arrive acutely unwell after deliberate self-poisoning
with large ingestions should be managed palliatively as soon as
the diagnosis is established.
• The aim of management in moderate and accidental ingestions is
to improve prognosis by reducing the dose that reaches the lungs
SPECIFIC TOXINS
through early decontamination and haemodialysis.
• Immediate management of airway, breathing and circulation is
rarely required. However, stridor, dysphagia and dysphonia
indicate airway injury and potential imminent airway compromise.
Early intubation or surgical airway is indicated in this setting.
• Do not administer supplemental oxygen unless oxygen saturation
<90%. Oxygen administration is titrated to achieve saturation not
>91%.
• General supportive care measures are indicated, as outlined in 347
Decontamination
• At the scene, administer food or soil to adsorb paraquat and
TOXICOLOGY HANDBOOK
reduce gastrointestinal absorption.
• Administer 50 g of activated charcoal (1 g/kg in children) PO
immediately on arrival at hospital.
• Fuller’s earth is a clay soil adsorbent that has been traditionally
used, but is now often not readily available and offers no
advantage over activated charcoal.
• Haemodialysis or haemoperfusion is considered with the greatest
urgency in patients near the threshold lethal dose (from about a
mouthful up to 0.25 mL/kg of 20% solution). It is not indicated for
minor exposures (splashes, licks or tastes) and will not prevent
fatal outcome following large deliberate self-poisoning ingestions.
• Haemodialysis and haemoperfusion may remove paraquat if
performed early before distribution to tissues. The time beyond
which dialysis is of benefit (due to distribution of paraquat to
tissues) is uncertain. Maximal benefit is attained if performed
within 2 hours but this intervention may be considered up to 4
hours post ingestion unless signs of severe toxicity are already
evident.
Antidotes
• None available.
• Note: Many adjunct therapies have been proposed, including
N-acetylcysteine, corticosteroids, vitamins C and E,
cyclophosphamide and salicylic acid. Studies to date are
hypothesis-generating and inconclusive. Given its safety, it is
ERRNVPHGLFRVRUJ
reasonable to commence all patients on N-acetylcysteine (see
Chapter 4.17: N-acetylcysteine). In addition, dexamethasone
(8 mg tds IV) and salicylic acid (100 mg/kg/day in divided doses)
may be considered as semi-experimental but mechanistically
plausible anti-inflammatory therapies.

• Patients who are clinically well 6–12 hours after exposure, without
oral burns and with a negative dithionite test, have not absorbed
paraquat systemically and may be discharged.
• Adult patients with moderate self-poisoning or accidental
ingestions should be managed in an intensive care setting. An
early paraquat level is useful in determining prognosis and utility
SPECIFIC TOXINS
of care.
• Patients with a history of massive ingestion (e.g. >100 mL of 20%
paraquat) and early clinical features of intoxication have a
hopeless prognosis and are managed palliatively from the outset.
HANDY TIP
• Immediate pre-hospital gastrointestinal decontamination with
anything that is available (food, soil, charcoal) may be life saving.
348 PITFALL
34
• Failure to advise carers to avoid oxygen unless there is profound

8
hypoxia.
TOXICOLOGY HANDBOOK
CONTROVERSIES
• The efficacy and indications for haemodialysis and the time
beyond which it is unlikely to provide any benefit.
• The role of immunosuppressive therapies such as
methylprednisolone and cyclophosphamide is not established.
• Predictive value of serum paraquat levels. They appear to be
more accurate at predicting death than survival.
Presentations
Paraquat alone: 6.4%, 20%, 24%, 25% w/v
Paraquat concentrate 36% has been discontinued but may still be accessible.
Paraquat–Diquat mixtures: 1.25% and 1.25%, 2.5% and 2.5%, 10% and 5%, 10% and
10%, 12.5% and 7.5%, 13.5% and 11.5%
Most products contain colouring (blue-green or red-brown) and stenching agents.
References
Dinis-Oliveira PJ, Duarte JA, Sanchez-Navarro A et al. Paraquat poisonings: mechanisms
of lung toxicity, clinical features and treatment. Critical Reviews in Toxicology 2008;
38:13–71.
Eddleston M, Wilks MF, Buckley NA. Prospects for treatment of paraquat-induced
lung fibrosis with immunosuppressive drugs and the need for better prediction
of outcome: a systematic review. Quarterly Journal of Medicine. 2003;
96(11):809–824.
Gawarammana IB, Buckley NA. Medical management of paraquat ingestion. British
Journal of Pharmacology 2011; 5:745–757.
Senarathna L, Eddleston M, Wilks MF. Prediction of outcome after paraquat poisoning
by measurement of the plasma paraquat concentration. Quarterly Journal of
Medicine 2009; 102:251–259.
ERRNVPHGLFRVRUJ
3.64 PHENOTHIAZINES AND BUTYROPHENONES
(antipsychotic agents)
Phenothiazines: Chlorpromazine, Fluphenazine, Pericyazine, Pipothiazine,
Prochlorperazine, Thioridazine, Trifluoperazine Butyrophenones:
Droperidol, Haloperidol
The antipsychotic (neuroleptic) agents cause CNS depression,
orthostatic hypotension, dystonias and anticholinergic effects in
overdose. Thioridazine, which was associated with cardiac conduction
abnormalities (increased QRS and QT intervals) and higher rates of
ventricular dysrhythmias, is now no longer marketed.
SPECIFIC TOXINS
RISK ASSESSMENT
• The antipsychotic agents cause dose-dependent CNS depression,
tachycardia, hypotension and anticholinergic effects.
• Chlorpromazine can cause coma requiring intubation and
ventilation with ingestions >5 g.
• Cardiac dysrhythmias are very uncommon, with the exception of
thioridazine in large doses.
• Seizures are uncommon after any dose.
349
• Children: lethargy, coma, agitation, tachycardia and
extrapyramidal effects may occur after small ingestions. Ingestion
of even one tablet warrants hospital observation. Extrapyramidal
TOXICOLOGY HANDBOOK
effects may develop up to 72 hours post ingestion.
Toxic mechanism
The major therapeutic action of the phenothiazines is mediated via central dopamine (D2)
antagonism. Their adverse effects are secondary to antagonist action at multiple other
receptors, including histaminic (H1), GABAA, muscarinic (M1), α1- and α2-adrenergic and
serotonergic (5-HT) receptors. Cardiotoxicity is secondary to sodium and potassium
channel blocking effects. The butyrophenones are a separate class of drug, but have
similar pharmacological and pharmacokinetic properties.
Toxicokinetics
The antipsychotics are rapidly absorbed following oral administration at therapeutic
doses and undergo extensive first-pass metabolism with variable bioavailability.
Absorption may be slow and erratic following overdose. Antipsychotics are lipid soluble
with large volumes of distribution. They undergo extensive hepatic metabolism by
cytochrome P450 enzymes. Many have active metabolites and prolonged elimination
half-lives. Chlorpromazine has early, intermediate and late elimination phases (2–3 hours,
11–15 hours and up to 60 days, respectively).
CLINICAL FEATURES
• Onset of clinical features of intoxication occurs within 2–4 hours
of overdose.
• Sedation, ataxia, orthostatic hypotension and tachycardia are
common.
• Fluctuating mental status with intermittent agitated delirium may
occur with moderate doses and usually lasts <24 hours.
• Urinary retention is common.
• Coma occurs following large ingestions of chlorpromazine and
may last from 18 to 48 hours.
ERRNVPHGLFRVRUJ
• Anticholinergic delirium may complicate recovery from coma.
• QT prolongation and torsades de pointes were characteristic of
thioridiazine overdose but are not clinically significant with other
agents.
• Seizures and extrapyramidal effects are uncommon.
INVESTIGATIONS
• If the 12-lead ECG is normal at 6 hours, further cardiac
monitoring is not required.
SPECIFIC TOXINS
MANAGEMENT
• Manage agitated delirium as outlined in Chapter 2.7: Delirium
and agitation.
350
35
0
Decontamination
• Activated charcoal is only administered after endotracheal
TOXICOLOGY HANDBOOK
intubation. It is withheld prior to intubation due to the risk of

imminent coma. Activated charcoal is not indicated for patients
without coma, as good outcome is expected with supportive
care.
Antidotes
• None available.
• Children are referred for hospital evaluation and observation
following suspected unintentional ingestion of any amount.
• Patients who are clinically well, with normal 12-lead ECG (or static
preexisting changes), normal mental status and normal vital signs
at 6 hours post ingestion may cease continuous cardiac
monitoring and are fit for medical discharge.
• Patients requiring intubation and ventilation are admitted to
intensive care. Anticholinergic delirium may predominate as coma
resolves, influencing decisions regarding safe extubation.
HANDY TIPS
• Hypotension is usually secondary to peripheral vasodilation and
responds well to infusion of IV crystalloid solution.
• Significant cardiotoxicity is not observed with phenothiazine
overdose now that thioridiazine is no longer available.
ERRNVPHGLFRVRUJ
Presentations
Chlorpromazine hydrochloride 10 mg Haloperidol decanoate 50 mg/1 mL
tablets (100) ampoules (for depot injection)
Chlorpromazine hydrochloride 25 mg Haloperidol decanoate 150 mg/3 mL
tablets (100) ampoules (for depot injection)
Chlorpromazine hydrochloride 100 mg Pericyazine 2.5 mg tablets (100)
tablets (100) Pericyazine 10 mg tablets (100)
Chlorpromazine hydrochloride 10 mg/mL Pipothiazine palmitate 50 mg/1 mL
mixture (100 mL) ampoules (for depot injection)
Chlorpromazine hydrochloride 25 mg/5 mL Pipothiazine palmitate 100 mg/2 mL
mixture (100 mL) ampoules (for depot injection)
Chlorpromazine hydrochloride 50 mg/2 mL Prochloperazine maleate 5 mg tablets (25)
ampoules Prochlorperazine maleate 25 mg
Droperidol 2.5 mg/1 mL ampoules suppositories (5)
SPECIFIC TOXINS
Fluphenazine hydrochloride 0.5 mg/1 mL Prochlorperazine mesylate 12.5 mg/1 mL
elixir (480 mL) ampoules
Fluphenazine decanoate 12.5 mg/0.5 mL Trifluoperazine hydrochloride 1 mg tablets
ampoule (100)
Fluphenazine decanoate 25 mg/1 mL Trifluoperazine hydrochloride 2 mg tablets
ampoule (100)
Fluphenazine decanoate 50 mg/2 mL Trifluoperazine hydrochloride 5 mg tablets
ampoule (100)
Haloperidol 0.5 mg tablets (100) Trifluoperazine hydrochloride 15 mg
Haloperidol 1.5 mg tablets (100) capsules (50)
Haloperidol 5.0 mg tablets (50) Trifluoperazine hydrochloride 1 mg/mL 351
Haloperidol 2 mg/1 mL liquid (100 mL) syrup (1000 mL)
Haloperidol 5 mg/1 mL ampoules
TOXICOLOGY HANDBOOK
References
James LP, Abel K, Wilkinson J et al. Phenothiazine, butyrophenone, and other
psychotropic medication poisonings in children and adolescents. Clinical Toxicology
2000; 38(6):615–623.
Strachan EM, Kelly CA, Bateman DN. Electrocardiographic and cardiovascular changes
in thioridiazine and chlorpromazine poisoning. European Journal of Clinical
Pharmacology 2004; 60:541–545.
3.65 PHENYTOIN
Phenytoin intoxication results from either repeated supratherapeutic
dosing or acute overdose. Intoxication is usually benign and results in
dose-related ataxia and CNS depression. Falls represent the greatest
danger to the majority of patients. Care is supportive.
RISK ASSESSMENT
• Dose-dependent CNS effects, mainly cerebellar, occur following
acute oral overdose (Table 3.65.1).
• Coma and seizures are rare, even with massive doses.
• Cardiovascular effects are not associated with ingestion of
phenytoin but are reported after rapid intravenous infusion of
excessive doses.
• Children: ingestion of one or two 100-mg tablets is insufficient to
cause symptoms and does not require referral for medical
assessment or observation.
ERRNVPHGLFRVRUJ
TABLE 3.65.1 Dose-related risk assessment: Phenytoin
overdose
Dose Effect
10–15 mg/kg Standard therapeutic loading dose
>20 mg/kg Ataxia, dysarthria and nystagmus
>100 mg/kg Potential for coma and seizures
Toxic mechanism
Phenytoin blocks sodium channels and suppresses membrane post-tetanic potentiation
SPECIFIC TOXINS
and hyperexcitability.
Toxicokinetics
Absorption is slow and erratic following oral overdose. Peak serum levels may be
delayed up to 24–48 hours. Volume of distribution is 0.6 L/kg and protein binding is high
(90%). Phenytoin undergoes hepatic hydroxylation (cytochrome P450 2C9) to form an
inactive metabolite. Metabolism is saturable (Michaelis-Menten kinetics) and plasma
levels and elimination half-life rise dramatically with small increases in daily dose.
Elimination half-lives in poisoned patients may vary from 24 to 230 hours. Cytochrome
P450 2C9 exhibits genetic polymorphism and there is inter-individual variation in
352 elimination rates.
35
2
CLINICAL FEATURES
• Chronic toxicity usually presents with gradual onset of ataxia.
TOXICOLOGY HANDBOOK
Dysarthria and nystagmus are also evident.

• Mild gastrointestinal symptoms may occur within 2 hours of acute
overdose.
• Onset of neurological toxicity develops slowly over hours
following acute overdose. Clinical features of toxicity include: slow
horizontal nystagmus, dysarthria, ataxia, tremor, vertical
nystagmus, drowsiness, involuntary movements and
ophthalmoplegia.
• Neurological symptoms of toxicity typically resolve over 2–4 days
as serum levels slowly fall.
• Coma, rigidity and seizures occur rarely and only after massive
overdose.
• Hypernatraemia and hyperglycaemia resulting in non-ketotic
hyperosmolar coma are reported after massive ingestion.
• Permanent cerebellar injury is rarely reported after prolonged and
severe intoxication.
• Rapid IV administration of phenytoin (and propylene glycol diluent)
is associated with hypotension, bradycardia, ventricular
dysrhythmias and asystole.
INVESTIGATIONS
• Serum phenytoin levels
— Useful to confirm the diagnosis.
ERRNVPHGLFRVRUJ
— Correlate with clinical toxicity:
– Nystagmus is associated with levels >20 mg/L
(80 micromol/L)
– Severe ataxia is associated with levels of 30–40 mg/L
(120–160 micromol/L)
– Coma is associated with levels >50 mg/L (200 micromol/L).
— In mild to moderate intoxication, management is guided by
clinical features; repeated levels are not required.
— Serial phenytoin levels are useful in severe intoxication to
monitor ongoing absorption and response to interventions.
MANAGEMENT
SPECIFIC TOXINS
• General supportive care as outlined in Chapter 1.4: Supportive
care and monitoring ensure a good outcome in the majority of
patients.
• Bed rails should be raised at all times and ambulation should be
initially only attempted with supervision.
• ECG monitoring is not necessary following oral phenytoin
overdose or for chronic phenytoin toxicity. 353
Decontamination
• Give activated charcoal to the cooperative patient who presents
TOXICOLOGY HANDBOOK
within 4 hours of acute oral overdose. This may reduce toxicity
and length of hospital stay.
• Multiple-dose activated charcoal may enhance elimination but
there is no evidence that outcome is improved; this intervention is
not routine.
• Charcoal haemoperfusion and plasmapheresis have been used in
severe phenytoin intoxication and may enhance elimination, but
are not routine.
Antidotes
• None available.
• Children may be observed at home following unintentional
exposures. Hospital assessment is only indicated if significant
ataxia or drowsiness develops.
• Patients with nystagmus, ataxia or drowsiness are managed
supportively in a ward environment.
• Patients with coma requiring intubation or seizures require
admission to the intensive care unit.
• Patients are medically fit for discharge as soon as they are able to
walk safely.
HANDY TIPS
• Consider the diagnosis of phenytoin toxicity in any patient on
chronic therapy who presents with difficulty walking.
ERRNVPHGLFRVRUJ
• It may take several days for phenytoin toxicity to resolve.
• Coma is rare in isolated phenytoin overdose. Other causes should
be considered and excluded.
PITFALLS
• Failure to order a phenytoin level in the patient on chronic therapy
who presents with ataxia or non-specific symptoms.
• Allowing a patient with phenytoin toxicity to fall during
unsupervised attempts at mobilisation.
CONTROVERSY
• Utility of techniques of enhanced elimination. These
techniques have not been demonstrated to provide any
SPECIFIC TOXINS
clinical benefit.
Presentations
Phenytoin sodium 30 mg capsules (200)
Phenytoin sodium 100 mg capsules (200)
Phenytoin 50 mg tablets (200)
Phenytoin 30 mg/5 mL suspension (500 mL)
Phenytoin sodium 100 mg/2 mL ampoules (contain propylene glycol diluent)
Phenytoin sodium 250 mg/5 mL ampoules (contain propylene glycol diluent)
354
References
35
4
Anonymous. Position statement and practice guidelines on the use of multi-dose

activated charcoal in the treatment of acute poisoning. Journal of Toxicology
TOXICOLOGY HANDBOOK
– Clinical Toxicology 1999; 37(6):731–751.

Craig S. Phenytoin poisoning. Neurocritical Care 2005; 3(2):161–170.
Curtis DL, Piibe R, Ellenhorn MJ et al. Phenytoin toxicity: a review of 94 cases. Veterinary
and Human Toxicology 1989; 31(92):164–165.
Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs
used to treat epilepsy. Quarterly Journal of Medicine 1998; 91:325–332.
Skinner CG, Chang AS, Matthew AR et al. Randomised controlled study on the use of
multiple-dose activated charcoal in patients with supratherapeutic phenytoin levels.
Wyte CD, Berk WA. Severe oral phenytoin overdose does not cause cardiovascular
morbidity. Annals of Emergency Medicine 1991; 20(5):510–512.
3.66 POTASSIUM CHLORIDE

Deliberate self-poisoning by ingestion of potassium chloride is rare but
can result in life-threatening hyperkalaemia and cardiac arrest. The
principal preparation of concern is slow-release potassium chloride,
which is available in bottles of 100 tablets without prescription. A good
outcome depends on early risk assessment, gastrointestinal
decontamination and haemodialysis where indicated.
RISK ASSESSMENT
• Small ingestions are usually benign in patients with normal renal
function.
• Ingestion of >2.5 mmol/kg of potassium may theoretically
temporarily overwhelm the capacity of the kidneys to excrete
potassium and lead to hyperkalaemia.
ERRNVPHGLFRVRUJ
• The lethal dose of KCl tablets (each containing 8 mmol KCl) in an
adult is not well defined.
• Massive ingestion (>40 × 600-mg tablets) prompts early planning
for haemodialysis in case severe hyperkalaemia cannot be
controlled by other means.
• Patients with renal impairment or cardiac disease may be at
higher risk.
• Abdominal X-ray assists risk assessment as slow-release
potassium tablets are radio-opaque.
• Children: ingestion of three 600-mg KCl tablets may cause
significant hyperkalaemia in a 10-kg toddler.
Toxic mechanism
SPECIFIC TOXINS
Potassium is the principal intracellular cation. Hyperkalaemia interferes with electrical
conduction in both nerve and muscle and, if severe, causes cardiac arrest. Potassium
salts have a direct irritant effect on the gastrointestinal mucosa when ingested.
Toxicokinetics
Potassium is rapidly absorbed from the small intestine. It is distributed to the
intracellular compartment. Potassium is excreted in the urine (90–95%), faeces and
sweat. Hyperkalaemia develops when the rate of absorption from the gut exceeds
the combined rates of redistribution to the intracellular compartment and urinary
excretion.
355
CLINICAL FEATURES
• Following overdose of potassium salts, GI symptoms including
TOXICOLOGY HANDBOOK
abdominal pain, nausea and vomiting are common and occur
early. Ileus and mucosal perforation may occur.
• As hyperkalaemia progresses (serum potassium 6–8 mmol/L),
lethargy, confusion, weakness, paraesthesia and hyporeflexia
develop.
• Paralysis and bradycardia herald cardiac arrest (serum K
>8 mmol/L).
INVESTIGATIONS
• Serial 12-lead ECGs demonstrate a progression of abnormalities
as serum potassium rises: peaked T waves (plasma K
>6.0 mmol/L), PR prolongation, loss of P waves with atrial
paralysis, widening of QRS, QT prolongation, sine wave
appearance and finally asystole.
• EUC with serial potassium concentrations.
• Abdominal X-ray. Useful to confirm number of slow-release
potassium chloride tablets ingested. Serial X-rays also have a role
in monitoring success of decontamination.
MANAGEMENT
Refer to Chapter 1.2: Resuscitation.
ERRNVPHGLFRVRUJ
• Initial efforts are directed at detecting a rising serum potassium
and acting to achieve temporary control while arrangements are
made for urgent haemodialysis.
• Obtain an urgent serum potassium level and control
hyperkalaemia aggressively:
— Calcium chloride 10 mL 10% (0.15 mL/kg in children) IV
through a running line
— Nebulised salbutamol 10–20 mg (in children 2.5 mg if <5 years
or 5 mg if >5 years)
— Dextrose 50 mL 50% and insulin 10 U IV (10 mL/kg 10%
dextrose and insulin 0.1 U/kg in children)
— Sodium bicarbonate 50–100 mmol slow IV (1 mmol/kg in
children).
• General supportive care measures including adequate intravenous
SPECIFIC TOXINS
fluids to maintain urine output are indicated, as outlined in

Decontamination
• Activated charcoal does not bind potassium chloride and is not
indicated.
• Slow-release potassium chloride tablets are amenable to removal
by whole bowel irrigation (WBI). However, decontamination
cannot be achieved rapidly enough to prevent lethal
356
hyperkalaemia following large overdoses. Institution of WBI must
35
never delay initiation of haemodialysis if it is indicated. The chief

6
value of WBI lies in completing decontamination once

TOXICOLOGY HANDBOOK
hyperkalaemia has been controlled with haemodialysis.

• Haemodialysis is the definitive treatment of hyperkalaemia
following massive potassium chloride overdose. Initiation of
haemodialysis provides immediate control of hyperkalaemia.
Haemodialysis must be started before hyperkalaemic cardiac
arrest occurs.
• Planning for haemodialysis begins at the risk assessment stage
and is indicated if:
— Ingested dose >40 × 600-mg KCl tablets confirmed on X-ray
— Renal impairment
— Cardiovascular instability
— Serum potassium >8.0 mmol/L
— Rapidly rising serum potassium.
• Haemodialysis continues until decontamination of the
gastrointestinal tract with WBI is confirmed on X-ray.
• Serum potassium is monitored closely after haemodialysis is
ceased. A rising potassium indicates incomplete decontamination,
ongoing absorption and the need to reinstitute haemodialysis.
Antidotes
• None. A number of pharmacological interventions are useful to
provide temporary control of hyperkalaemia (see above).

• Patients demonstrating toxicity or having ingested a toxic dose
are managed in a critical care area with dialysis facilities.
ERRNVPHGLFRVRUJ
• Patients are medically fit for discharge once decontamination is
complete and serum potassium is stable off haemodialysis.
HANDY TIPS
• Slow-release potassium chloride tablets are radio-opaque.
• Massive potassium ingestion is potentially lethal. Measures to
reduce serum potassium do not constitute definitive care. They
are initiated only in an effort to provide sufficient time for the
patient to receive definitive care with haemodialysis.
• Resonium A (cation exchange resin) 20–50 g (0.5–1.0 g/kg in
children) binds only 1 mmol of potassium per gram. It is not
useful following massive slow-release potassium chloride
overdose.
SPECIFIC TOXINS
CONTROVERSY
• Indications for haemodialysis and WBI.
Presentations
Potassium chloride 600 mg (8 mmol KCl) slow-release tablets (100)
Reference
Su M, Stork C, Ravuri S et al. Sustained-release potassium chloride overdose. Clinical
Toxicology 2001; 39(6):641–648. 357
3.67 QUETIAPINE
TOXICOLOGY HANDBOOK
Quetiapine is a second-generation atypical antipsychotic agent.
Deliberate self-poisoning is associated with sedation, delirium, coma,
tachycardia and hypotension. It is currently a leading cause of toxic
coma requiring intensive care admission. Thorough supportive care
ensures a good outcome.
RISK ASSESSMENT
• Quetiapine intoxication is associated with predictable dose-
dependent CNS depression ranging from sedation to coma and a
characteristic brisk tachycardia (see Table 3.67.1).
• Mild hypotension is sometimes observed. It may be profound with
massive ingestion.
• Minor QT prolongation may occur but there are no reports of
torsades de pointes.
TABLE 3.67.1 Dose-related risk assessment: Quetiapine
Dose Effect
<3 g Mild-to-moderate sedation and sinus tachycardia

(frequently >120 beats/minute)
>3 g Increasing risk of CNS depression, coma and hypotension

Delirium and seizures may occur
ERRNVPHGLFRVRUJ
• Co-ingestion of ethanol or other sedative-hypnotic agents
increases the risk of coma and loss of airway protective
reflexes.
• Children: extrapolation from adult data and paediatric experience
with other atypical antipsychotic agents suggests that sedation,
tachycardia and delirium may occur with ingestion of >100 mg.
Toxic mechanism
Quetiapine is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5-HT2A),
histaminic (H1), muscarinic (M1) and peripheral alpha (α1) receptors.
Toxicokinetics
Quetiapine is rapidly but incompletely absorbed. It is lipid soluble and highly protein
bound, with a large volume of distribution (10 L/kg). Quetiapine is almost completely
SPECIFIC TOXINS
metabolised by hepatic cytochrome P450 3A4 to an active metabolite,

7-hydroxyquetiapine.
CLINICAL FEATURES
• Onset of clinical features of intoxication occurs within 2–4 hours
and may last 24–72 hours.
• Sedation and sinus tachycardia are common.
• Coma, if it occurs, usually lasts from 18–48 hours.
358 • Hypotension.
• Clinically significant QT prolongation is rare and torsades de
35
pointes is not reported.

8
• Seizures occur in <5 % of cases.

TOXICOLOGY HANDBOOK
INVESTIGATIONS
• Serial 12-lead ECG.
• Sinus tachycardia is frequently seen.
• An ECG should be performed at presentation and after 4 hours
(and again at 8 hours following ingestion of modified-release
preparations). If it remains normal at that time, ECG monitoring is
ceased in patients not requiring intubation.
• In intubated patients, 12-lead ECGs are assessed for QT
prolongation every 4 hours until clinical improvement occurs.
MANAGEMENT
• Hypotension should initially be treated with fluid administration.
Give 10–20 mL/kg IV crystalloid. If the response is inadequate,
commence an infusion of noradrenaline and titrate to response.
• Severe agitated delirium is managed with titrated doses of
intravenous diazepam, as outlined in Chapter 2.7: Delirium and
agitation.
ERRNVPHGLFRVRUJ
Decontamination
• The onset of sedation and coma occurs in the first few hours.
Thorough supportive care ensures a good outcome. Therefore,
activated charcoal is not indicated unless the airway is first
Antidotes
• None available.
• Children are observed in hospital following unintentional ingestion
SPECIFIC TOXINS
of >100 mg quetiapine or if any symptoms develop. If they remain
clinically well without sedation at 4 hours (8 hours following
ingestion of modified-release preparations), they may be
discharged. Parents are advised that abnormal (extrapyramidal)
movements might occur up to 3 days after ingestion.
• Patients who have ingested <3 g and are clinically well, not
sedated and have normal 12-lead ECG at 4 hours (8 hours
following ingestion of modified-release preparations) do not
require further medical assessment or monitoring.
359
• Patients who have ingested >3 g, or manifest clinical features of
intoxication, require admission for appropriate supportive care.
TOXICOLOGY HANDBOOK
HANDY TIPS
• Sinus tachycardia exceeding 120 beats/minute is usual. No
specific intervention is required.
• Adrenaline infusion may paradoxically exacerbate the hypotension
of quetiapine toxicity. This is thought to be due to excessive
β2-mediated vasodilation. Noradrenaline is the preferred inotropic
agent and an excellent response is usually observed.
CONTROVERSY
• The agitated delirium associated with quetiapine intoxication is
likely to be of central anticholinergic origin; however, the role of
physostigmine is yet to be determined.
Presentations
Quetiapine 25 mg tablets (60)
Quetiapine 50 mg modified-release tablets (60)
Quetiapine 300 mg modified-release tablets (60, 100)
References
Balit CR, Isbister GK, Hackett LP. Quetiapine: a case series. Annals of Emergency
Medicine 2003; 42:751–758.
ERRNVPHGLFRVRUJ
Hawkins DJ, Unwin P. Paradoxical and severe hypotension in response to adrenaline
infusion in massive quetiapine overdose. Critical Care and Resuscitation 2008;
10(4):320–322.
Ngo A, Ciranni M, Olson KR. Acute quetiapine overdose in adults: a 5-year retrospective
case series. Annals of Emergency Medicine 2008; 52:541–547.
Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical
antipsychotic medication overdose. American Journal of Emergency Medicine 2009;
27:607–616.
3.68 QUININE
SPECIFIC TOXINS
Quinine toxicity is characterised by ‘cinchonism’, consisting of nausea,

vomiting, tinnitus, vertigo and deafness. Larger overdoses may result in
life-threatening cardiotoxicity and severe, potentially permanent, visual
disturbance.
RISK ASSESSMENT
• All cases of deliberate self-poisoning should be regarded as
having the potential to cause cardiotoxicity and delayed visual
disturbance.
360 • Ingestion of >1 g usually produces some degree of cinchonism.
• Cardiotoxicity, CNS disturbances and blindness are more
36
0
commonly observed when the ingested dose is >5 g and almost

universal if >10 g.
TOXICOLOGY HANDBOOK
• Children: ingestion of 600 mg (two tablets) by a child <6 years

old has the potential to cause life-threatening toxicity.
Toxic mechanism
Quinine is a class 1A antidysrhythmic with corresponding sodium channel and potassium
rectifier channel blocking functions. It results in prolongation of both the QRS and QT
intervals. In overdose, quinine is directly toxic to the retina. Quinine also stimulates
pancreatic insulin release in a manner similar to sulfonylureas.
Toxicokinetics
Quinine is rapidly absorbed from the small intestine with a bioavailability of
approximately 70%. It is highly protein bound in adults but less so in children; this may
explain the relative vulnerability of the paediatric population. Elimination half-life may
be prolonged to >24 hours in overdose. Elimination is largely via hydroxylation with
approximately 20% being excreted unchanged in the urine. Quinine does not undergo
enterohepatic circulation.
CLINICAL FEATURES
• Cinchonism
— Characterised by nausea, vomiting, alterations in hearing,
tinnitus, and vertigo.
— Occurs early following overdose and resolves as blood
quinine concentration falls.
• Cardiovascular
— Hypotension, sinus tachycardia, QRS widening and
prolongation of the QT and PR intervals.
— Wide-complex tachycardia and torsades de pointes are
reported.
ERRNVPHGLFRVRUJ
— These effects usually occur relatively early (within 8 hours) and
resolve as blood quinine concentration falls.
— Drowsiness and confusion are observed with larger
ingestions.
— Coma and seizures are rare.
• Eyes
— Onset of visual disturbance is delayed and usually not
apparent until 6–8 hours post ingestion. It is often not
detected until the next morning when the patient wakes up.
— Manifestations include blurring, disturbances in colour
perception, pupillary dilation and visual field constriction.
Complete blindness develops in severe cases.
— Recovery of visual disturbance usually occurs over days to
SPECIFIC TOXINS
weeks, although permanent residual deficits do occur. These
are more likely in patients who develop complete blindness
during the acute phase.
INVESTIGATIONS
Specific investigations as indicated 361
• EUC, formal visual field mapping
• Quinine blood levels: These correlate well with toxicity (>10 mg/L
TOXICOLOGY HANDBOOK
at 6 hours is associated with cardiovascular toxicity and visual
disturbance) but are not available in a clinically relevant time
frame and do not assist clinical decision making.
MANAGEMENT
— Coma
– Urgent intubation and ventilation is indicated.
— Wide-complex tachydysrhythmias
– Immediate intubation and hyperventilation, and serum
alkalinisation with sodium bicarbonate are indicated (see
Chapter 4.24: Sodium bicarbonate for details on
administration).
– Correct hypoxia and hypokalaemia and administer
magnesium sulfate 10 mmol (0.05 mmol/kg in children)
IV over 15 minutes. If heart rate is <100 beats/minute
commence an isoprenaline infusion IV at 1–10
microgram/min (0.05–2.0 microgram/kg/min in children)
or overdrive pacing to maintain heart rate at 100–120
beats/minute.
— Seizures
– Control with titrated intravenous benzodiazepines, as
described in Chapter 2.6: Seizures.
ERRNVPHGLFRVRUJ
Chapter 1.4: Supportive care and monitoring. Intravenous fluids
and antiemetics are always required for the supportive care of
cinchonism. The blind patient will require particular assistance,
potentially for days or weeks.
Decontamination
• Administer 50 g activated charcoal to all overdose patients who
are awake and able to drink the charcoal slurry themselves.
Antiemetics may aid administration. If there is significant CNS
depression or seizures, activated charcoal is only administered by
nasogastric tube after the airway is secured by endotracheal
intubation.
SPECIFIC TOXINS
• Multiple-dose activated charcoal is demonstrated to substantially
enhance the elimination of quinine. This intervention is indicated
in any patient who has ingested >5 g of quinine or who has any
degree of visual disturbance.
Antidotes
• None available.
362 DISPOSITION AND FOLLOW-UP
•
36
All children who are suspected of ingesting 600 mg or more of

2
quinine must be observed and monitored for 6 hours post

ingestion.
TOXICOLOGY HANDBOOK
• All patients who deliberately self-poison with quinine should be

observed and monitored for at least 6 hours.
• Patients who are asymptomatic and have a normal ECG at 6
hours following ingestion are cleared for medical discharge.
• Patients with symptoms or an abnormal ECG must be admitted
for ongoing observation and monitoring until symptoms resolve.
• All patients with quinine toxicity must have careful assessment of
vision prior to medical clearance. Those patients with abnormal
vision or visual fields require ophthalmological review and
follow-up.
• Patients who develop coma, seizures, an abnormal ECG or
cardiac dysrhythmia during the initial 6 hours observation are
admitted to an intensive care unit.
HANDY TIPS
• Consider quinine overdose in any patient with deliberate self-
poisoning who complains of visual disturbance.
• Anticipate the onset of visual disturbance in any patient who has
ingested >5 g of quinine. The patient’s vision should be carefully
assessed the morning following admission.
PITFALL
• Failure to warn the patient that visual disturbance may
develop 6–8 hours later. It is very disturbing for the patient to
awake the following morning and unexpectedly discover they
are blind.
ERRNVPHGLFRVRUJ
CONTROVERSY
• It was previously believed that the visual disturbance was a
complication of retinal arterial vasospasm. Various interventions
including vasodilators, stellate ganglion blocks and hyperbaric
oxygen therapy were used in attempts to prevent blindness. It
now appears that the blindness occurs from direct retinal toxicity
and cannot be prevented by any of these interventions. Attempts
at decontamination and enhanced elimination with multiple-dose
activated charcoal offer the best chance of minimising retinal
toxicity.
Presentations
Quinine bisulfate 300 mg (50)
SPECIFIC TOXINS
Quinine dihydrochloride 600 mg/10 mL ampoules
Quinine sulfate 300 mg (50)
References
Boland ME, Roper SM, Henry JA. Complications of quinine poisoning. Lancet 1985;
1(8425):384–385.
Guly U, Driscoll P. The management of quinine-induced blindness. Archives of
Huston M, Levinson M. Are one or two dangerous? Quinine and quinidine exposure in
toddlers. Journal of Emergency Medicine 2006; 31(4):395–401.
Langford NJ, Good AM, Laing WJ et al. Quinine intoxications reported to the Scottish 363
Poisons Information Bureau 1997–2002: a continuing problem. British Journal of
Clinical Pharmacology 2003; 56:576–578.
TOXICOLOGY HANDBOOK
3.69 RISPERIDONE
Deliberate self-poisoning with this atypical antipsychotic agent is
associated with tachycardia and acute dystonic reactions. CNS
depression is unusual and rarely significant. Supportive care ensures a
good outcome.
RISK ASSESSMENT
• The dose–effect profile is not well defined.
• Common clinical features of toxicity include sinus tachycardia
(50%) and acute dystonia (10%).
• CNS depression is rare when risperidone is taken alone.
• Children: ingestion of >1 mg is associated with clinical features of
toxicity. Acute dystonic reactions are more frequent following
paediatric exposure and frequently delayed.
Toxic mechanism
Risperidone is an antagonist at mesolimbic dopamine (D2), serotonin (particularly 5-HT2A),
alpha (α2) and peripheral alpha (α1) receptors. Compared with other antipsychotic agents
in its class, it has much lower affinity for histamine (H1) and muscarinic (M1) receptors.
Toxicokinetics
Risperidone is rapidly and well absorbed after oral administration. It is highly protein
bound and has a moderate volume of distribution (1.5 L/kg). Risperidone undergoes
hepatic metabolism by oxidation (cytochrome P450 2D6) to an active metabolite
(9-hydroxyrisperidone), which is eliminated by the kidneys. Renal impairment prolongs
the elimination half-life.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
• The onset of clinical features of intoxication is rapid and usually
occurs within 4 hours.
• Sinus tachycardia is common.
• Mild sedation may be observed but is uncommon.
• Miosis and mydriasis are reported.
• Acute dystonias occur frequently.
• QT prolongation may occur but torsades de pointes is not reported.
• Clinical features of toxicity resolve within 24 hours.
INVESTIGATIONS
SPECIFIC TOXINS

• Serial ECGs
— Perform an ECG at presentation and at 4 hours.
— Sinus tachycardia is common.
— Prolongation of the QT interval is reported but is not sufficient
in magnitude to pose a risk of torsades de pointes (see
Figure 2.20.4).
364
MANAGEMENT
36

4

TOXICOLOGY HANDBOOK

• Acute resuscitation is unlikely to be necessary unless there are
co-ingestions.
Decontamination
• Activated charcoal is not routinely indicated.
Antidotes
• Benztropine may be required to treat acute dystonia.
• All symptomatic children and those thought to have ingested
>1 mg should be referred for hospital assessment and observation.
• Patients who are clinically well, not sedated and have a normal
12-lead ECG at 4 hours may be medically cleared.
• Symptomatic patients are admitted for supportive care until all
clinical features of toxicity resolve.
• Cardiac monitoring is not indicated beyond 4 hours post ingestion
unless the QT interval is prolonged.
• At discharge, parents should be advised that abnormal
(extrapyramidal) movements might occur up to 3 days after
ingestion.
ERRNVPHGLFRVRUJ
HANDY TIP
• Coma, seizures or significant alteration in vital signs prompts
consideration of alternative diagnoses and revision of the risk
assessment.
PITFALL
• Failure to warn parents of the possibility of delayed abnormal
(extrapyramidal) movements after unintentional paediatric
exposure.
Presentations
Risperidone 0.5 mg tablets (20, 60)
Risperidone 1 mg tablets (60)
SPECIFIC TOXINS
Risperidone 0.5 mg orally disintegrating tablets (28)
Risperidone 1 mg orally disintegrating tablets (28)
Risperidone 1 mg/mL solution (30 mL, 100 mL)
Risperidone 25 mg extended-release microspheres with 2 mL solvent pre-filled
syringe 365
Risperidone 37.5 mg extended-release microspheres with 2 mL solvent pre-filled
syringe
Risperidone 50 mg extended-release microspheres with 2 mL solvent pre-filled
TOXICOLOGY HANDBOOK
syringe
References
Cobaugh DJ, Erdman AR, Booze LL et al. Atypical antipsychotic medication poisoning:
an evidence based consensus guideline for out-of-hospital management. Clinical
Toxicology 2007; 45(8):918–942.
Page CB, Calver LA, Isbister GK. Risperidone overdose causes extrapyramidal effects
but not cardiac toxicity. Journal of Clinical Psychopharmacology 2010; 30:387–390.
Tan HH, Hoppe J, Heard K. A systematic review of cardiovascular effects after atypical
antipsychotic medication overdose. American Journal of Emergency Medicine 2009;
27:607–616.
3.70 SALICYLATES
Acetylsalicylic acid (aspirin), Methyl salicylate
Acute intoxication presents with classical symptoms of vomiting, tinnitus,
hyperventilation, respiratory alkalosis and metabolic acidosis. Severe
toxicity may result in coma and seizures. Chronic intoxication presents
with non-specific clinical features and the diagnosis is frequently missed.
Morbidity and mortality are greater in chronic intoxication. Urinary
alkalinisation and haemodialysis are highly effective methods of
enhancing elimination.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• The severity of clinical features following acute aspirin overdose
is dose-related (see Table 3.70.1) and progresses over hours.
• Chronic poisoning has an increased risk of an adverse
outcome.
• In terms of the salicylate dose, 5 g of methyl salicylate is
equivalent to 7.5 g of acetylsalicylate (i.e. 1 mL of ‘oil of
wintergreen’ is equivalent to 1400 mg of aspirin).

acetylsalicylic acid (aspirin) overdose
SPECIFIC TOXINS
Dose Effect
<150 mg/kg Minimal symptoms
150–300 mg/kg Mild-to-moderate intoxication

Salicylism with hyperpnoea, tinnitus, vomiting
>300 mg/kg Severe intoxication

366 Metabolic acidosis, altered mental state, seizures
36
>500 mg/kg Potentially lethal

6
TOXICOLOGY HANDBOOK
• Children: rarely ingest a dose of aspirin sufficient to cause

toxicity but small ingestions of methyl salicylate-containing
products are sufficient to cause severe toxicity, for example
>5 mL of oil of wintergreen may cause serious toxicity and even
death in a child <6 years of age. Chronic salicylism has been
reported in the context of regular use of choline salicylate-
containing teething gels in infants.
Toxic mechanism
Salicylates cause irreversible inhibition of cyclooxygenase enzymes resulting in
decreased prostaglandin synthesis. Stimulation of the respiratory centre causes
hyperventilation and respiratory alkalosis. Uncoupling of oxidative phosphorylation results
in accumulation of lactic acid, contributing to metabolic acidosis. Promotion of fatty acid
metabolism and generation of ketone bodies also contributes to metabolic acidosis.
Death is associated with very high salicylate levels in the CNS.
Toxicokinetics
Salicylates are rapidly absorbed following oral administration and highly protein bound,
with a volume of distribution of 0.1–0.3 L/kg. Absorption may be delayed with enteric-
coated forms or if large tablet masses form within the stomach (‘bezoars’). In overdose,
protein binding is saturated and free salicylate increases. In acidaemia, more salicylate is
un-ionised, favouring movement into extravascular spaces, including the CNS.
Salicylates undergo hepatic metabolism. Kinetics change from first order to zero order in
overdose, as metabolic pathways become saturated. The elimination half-life of 2–4
hours in normal therapeutic dosing is prolonged up to 24 hours following overdose.
Urinary pH affects renal elimination. High urinary pH promotes urinary salicylate
excretion, as a greater proportion of salicylate is ionised and unable to be reabsorbed
across the renal tubular epithelium.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
Acute salicylate intoxication
• Onset of clinical features is progressive over hours and severe
toxicity may not be evident until 6–12 hours following ingestion.
Deterioration may then be very rapid.
— Nausea, vomiting
— Tinnitus, decreased hearing, vertigo
— CNS stimulation, agitation, seizures
— May progress to cerebral oedema and death
• Acid–base disturbance
— Respiratory alkalosis
SPECIFIC TOXINS
— Elevated anion gap metabolic acidosis
— Actual acidaemia occurs late and indicates imminent demise
without intervention
• Other
— Hyperthermia, hyper/hypoglycaemia, hypokalaemia
Chronic salicylate intoxication
• Difficult to diagnose clinically and often missed.
• Most common in elderly patients.
• Often presents with non-specific symptoms such as confusion, 367
delirium, dehydration, fever and unexplained metabolic acidosis.
• Cerebral and pulmonary oedema are more common than in acute
poisoning.
TOXICOLOGY HANDBOOK
INVESTIGATIONS
• Salicylate level
— Therapeutic range is 1.1–2.2 mmol/L (15–30 mg/dL,
150–300 mg/L).
— Levels correlate poorly with severity of toxicity.
— Serial levels every 2–4 hours are useful to identify ongoing or
delayed absorption from a tablet bezoar or slow-release
tablets.
— Detect and monitor acid–base disturbances.
• UEC
— Detect and correct hypokalaemia prior to urinary alkalinisation.
MANAGEMENT
• If intubation and ventilation are required for coma or respiratory
insufficiency, ensure controlled hyperventilation is implemented in
order to maintain respiratory alkalosis.
• Control seizures with intravenous benzodiazepines, as detailed in
ERRNVPHGLFRVRUJ
• Ensure sufficient fluid replacement with intravenous crystalloid to
account for gastrointestinal and insensible losses.
Decontamination
• Administer oral activated charcoal 50 g up to 8 hours following
acute overdose of >150 mg/kg. Following ingestion of >300 mg/
kg, administer activated charcoal 50 g via a nasogastric tube,
after first securing the airway if necessary. In either case, a
second dose of activated charcoal 50 g is indicated after 4 hours
if serum salicylate levels continue to rise.
• Urinary alkalinisation is indicated in patients with symptomatic
salicylate poisoning. Further details on the rationale and use of
SPECIFIC TOXINS
this intervention are provided in Chapter 1.7: Enhanced

elimination and Chapter 4.25: Sodium bicarbonate.
• Haemodialysis effectively removes salicylate but is rarely required
if early decontamination and urinary alkalinisation are
implemented. Consider this intervention in the following
circumstances:
— Urinary alkalinisation not feasible
— Serum salicylate levels rising to >4.4 mmol/L (>60 mg/dL,
>600 mg/L) despite decontamination and urinary
368 alkalinisation
36
— Severe toxicity as evidenced by altered mental status,

8
acidaemia or renal failure

— Very high serum salicylate levels:
TOXICOLOGY HANDBOOK
– Acute poisoning >7.2 mmol/L (>100 mg/dL, >1000 mg/L)

– Chronic poisoning >4.4 mmol/L (>60 mg/dL, >600 mg/L).
— The threshold to dialyse is lower in the elderly >4.4 mmol/L
(>60 mg/dL, >600 mg/L).
Antidotes
• None available.
• All children suspected of ingesting methyl salicylate products
should be observed in hospital for signs of salicylate toxicity for
at least 6 hours.
• All symptomatic patients require admission for careful monitoring
and enhanced elimination techniques. Therapy is ceased when
salicylate level falls to within the normal range (1.1–2.2 mmol/L,
15–30 mg/dL, 150–300 mg/L) and the clinical features and
acid–base abnormalities have resolved.
• Patients with significant toxicity are admitted to an intensive care
or high-dependency unit.
HANDY TIPS
• Urgent haemodialysis is indicated in any patient who requires
intubation for salicylate poisoning (but not if intubated because of
co-ingestants).
• Consider salicylate toxicity and order a serum salicylate level in
any elderly patient with altered mental status and metabolic
acidosis.
ERRNVPHGLFRVRUJ
• Although salicylate classically causes an elevated anion gap
metabolic acidosis, many bedside gas machines record a normal
or low anion gap by mistaking salicylate ions for chloride.
PITFALLS
• Failure to appreciate the potential for ongoing delayed absorption
from the gastrointestinal tract.
• Failure to maintain alkalaemia after intubation and ventilation,
leading to catastrophic clinical deterioration due to rapid
redistribution of salicylate to the CNS.
• Failure to identify ‘oil of wintergreen’ as methyl salicylate and
determine aspirin equivalence when constructing a risk
assessment.
• Failure to diagnose chronic aspirin poisoning.
SPECIFIC TOXINS
• Confusion between standard and SI units for salicylate
concentration.
Presentations
Aspirin 100 mg tablets (30, 90, 112)
Aspirin 100 mg enteric coated tablets (28, 84, 140, 168)
Aspirin 300 mg dispersible tablets (24, 42, 48, 60, 96)
Aspirin 320 mg tablets (20)
Aspirin 500 mg dispersible tablets (16, 120)
Aspirin 650 mg tablets (100)
369
Aspirin 100 mg/clopidogrel 75 mg tablets (30)
Aspirin 300 mg/codeine 8 mg dispersible tablets (60)
Aspirin 25 mg/dipyridamole 200 mg controlled release tablets (60)
TOXICOLOGY HANDBOOK
Methyl salicylate is found in oil of wintergreen (98% methyl salicylate) and various
products marketed for topical application, including certain Asian herbal remedies.
References
Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. Journal of
O’Malley GF. Management of the salicylate poisoned patient. Emergency Medicine
Clinics of North America 2007; 25(2):333–336.
Pearlman BL, Gambhir R. Salicylate intoxication: a clinical review. Postgraduate Medicine
2009; 121(4):162–168.
3.71 SELECTIVE SEROTONIN REUPTAKE

INHIBITORS (SSRIs)
Citalopram, Escitalopram, Fluoxetine, Fluvoxamine, Paroxetine, Sertraline
Deliberate self-poisoning with the selective serotonin reuptake inhibitors
(SSRIs) is common and usually follows a benign course. Serotonin
toxicity develops in a small minority. Among the SSRIs, citalopram and
escitalopram appear to be unique in their ability to cause dose-
dependent QT interval prolongation.
RISK ASSESSMENT
• Overdose with SSRIs is usually benign, irrespective of dose.
• Mild symptoms of serotonin toxicity occur in less than 20% of
patients and usually last <12 hours.
ERRNVPHGLFRVRUJ
• Seizures occur in <4% of patients and are more likely with
citalopram.
• Ingestion of >600 mg citalopram or >300 mg escitalopram is
associated with QT prolongation but torsades de pointes occurs
rarely.
• Co-ingestion of other serotonergic agents, such as monoamine
oxidase inhibitors, venlafaxine, bupropion or tramadol, greatly
increases the risk of severe serotonin syndrome.
• Children: unintentional paediatric ingestion of up to 3 tablets is
benign and referral to hospital is not required unless symptoms
develop.
Toxic mechanism
SPECIFIC TOXINS
The SSRIs enhance central serotonergic neurotransmission by inhibiting serotonin

reuptake. They have little affinity for adrenergic, dopaminergic, cholinergic, serotonergic
or histamine receptors.
Toxicokinetics
The SSRIs are rapidly absorbed following oral administration. They are protein bound
and have large volumes of distribution. They undergo hepatic metabolism to form less
active and water-soluble metabolites. Didesmethylcitalopram is the metabolite of
citalopram thought to be responsible for QT prolongation. Elimination half-lives are
approximately 24 hours.
370
CLINICAL FEATURES
37
•
0
Many patients remain asymptomatic.

• Minor symptoms usually begin within 4 hours and resolve within
TOXICOLOGY HANDBOOK
12 hours.
• Nausea is common.
• Mild serotonin syndrome occurs in less than 20% and manifests
as anxiety, tremor, tachycardia, bradycardia and mydriasis (see
Chapter 2.8: Serotonin syndrome). Severe serotonin syndrome
does not develop unless there is co-ingestion of other
serotonergically active drugs.
• Seizures are uncommon and most strongly associated with
citalopram and escitalopram (incidence about 2%) and usually
heralded by increased anxiety, sweating, tremor, tachycardia and
mydriasis. They are short-lived and easily controlled with
benzodiazepines.
• QT prolongation occurs after citalopram and escitalopram
overdose and is dose-dependent. There are rare reports of
cardiac dysrhythmias (wide-complex bradycardia and torsades de
pointes) following citalopram overdose.
INVESTIGATIONS
— Dose-dependent prolongation of the QT interval is described
in citalopram intoxication, with 68% of patients having QTc
>440 ms and 12% >500 ms in one series. QT prolongation is
also described with escitalopram intoxication.
ERRNVPHGLFRVRUJ
— Following citalopram overdose of >600 mg or escitalopram
overdose of >300 mg, perform a 12-lead ECG at presentation
and continue cardiac monitoring for at least 8 hours post
ingestion.
— Monitoring should continue until any risk of torsades de
pointes, as predicted by plotting a nomogram of QT against
heart rate, resolves (see Figure 2.20.4).
— If >1000 mg citalopram or >500 mg escitalopram is ingested,
continue ECG monitoring until 12 hours post ingestion, prior
to a decision based on a 12-lead ECG performed at that time.
MANAGEMENT
SPECIFIC TOXINS
Refer to Chapter 1.2: Resuscitation.
• Seizures and agitation are managed with benzodiazepines, as
outlined in Chapter 2.6: Seizures and Chapter 2.7: Delirium and
agitation.
• Management of serotonin syndrome is discussed in Chapter 2.8:
Serotonin syndrome.
• Increasing anxiety, sweating, tremor, tachycardia and mydriasis 371
may herald the onset of seizures. Administer IV diazepam 5 mg
every 2–5 minutes until gentle sedation is achieved and the heart
rate falls towards 100 beats/minute.
TOXICOLOGY HANDBOOK
• Continuous cardiac monitoring continues for 8 hours following
ingestion of >600 mg citalopram or >300 mg escitalopram, and 12
hours following ingestion of >1000 mg of citalopram or >500 mg
escitalopram. If the QT suggests no risk of torsades de pointes at
that time, monitoring may cease.
Decontamination
• Alert and cooperative patients who have ingested >600 mg
citalopram or >300 mg escitalopram may drink 50 g of activated
charcoal if it can be administered within 4 hours after the
overdose.
• Overdose with other SSRIs has an excellent outcome with
minimal supportive care; activated charcoal is not indicated
unless warranted by co-ingestants.
Antidotes
• None available.
• Paediatric patients may be observed at home following possible
unintentional exposure. If significant symptoms occur, referral to
hospital for supportive care is appropriate.
• Patients are observed with cardiac monitoring in place for at least
8 hours after ingestion of >600 mg citalopram or >300 mg
escitalopram and 12 hours after ingestion of >1000 mg of
ERRNVPHGLFRVRUJ
citalopram or >500 mg escitalopram. Monitoring should continue
if significant abnormalities are detected (see Chapter 2.20: The
12-lead ECG in toxicology).
• All other patients who deliberately self-poison with SSRIs are
observed for 6 hours. Asymptomatic patients with a normal ECG
are fit for medical discharge at the end of that time.
• Patients with clinical features of SSRI intoxication require
supportive care in a ward environment, usually for no more than
12–24 hours. They are fit for medical discharge as soon as clinical
features resolve.
• Patients who develop severe serotonin syndrome require
management in an intensive care unit.
SPECIFIC TOXINS
HANDY TIPS
• Coma indicates co-ingestion or complication and is not secondary
to SSRI intoxication.
• Citalopram and escitalopram are unique among the SSRIs in
causing dose-dependent QT prolongation. Cardiac dysrhythmias
are rare, but activated charcoal and ECG monitoring are indicated
as described above.
PITFALL
372
• Failure to administer benzodiazepines to patients with
37
increasing anxiety, sweating, tremor, tachycardia and

2
mydriasis.
TOXICOLOGY HANDBOOK
CONTROVERSY
• Activated charcoal reduces citalopram and escitalopram
absorption and decreases maximal QT prolongation. However,
given that torsades de pointes is extremely rare, the number
needed to treat with activated charcoal to prevent dysrhythmia is
not known.
Presentations
Citalopram hydrobromide 10 mg tablets (28)
Escitalopram oxalate 10 mg tablets (28)
Escitalopram oxalate 20 mg tablets (28)
Escitalopram oxalate 10 mg/mL oral solution (28 mL)
Fluvoxamine maleate 50 mg tablets (30)
Fluvoxamine maleate 100 mg tablets (30)
Fluoxetine hydrochloride 20 mg tablets (28)
Fluoxetine hydrochloride 20 mg capsules (28)
Paroxetine hydrochloride 20 mg tablets (30)
Sertraline hydrochloride 50 mg tablets (30)
Sertraline hydrochloride 100 mg tablets (30)
References
Hayes BD, Klein-Schwartz W, Clark RF, Muller AA, Miloradovich JE. Comparison of
toxicity of acute overdose with citalopram and escitalopram. Journal of Emergency
Medicine 2010; 39(1):44–48.
Isbister GK, Bowe SJ, Dawson A et al. Relative toxicity of selective serotonin reuptake
inhibitors (SSRIs) in overdose. Clinical Toxicology 2004; 42(3):277–285.
ERRNVPHGLFRVRUJ
Isbister GK, Friberg LE, Duffull SB. Application of pharmacokinetic-pharmacodynamic
modelling in the management of QT abnormalities after citalopram overdose.
Intensive Care Medicine 2006; 32(7):1060–1065.
Isbister GK, Friberg LE, Stokes B et al. Activated charcoal decreases QT prolongation
after citalopram overdose. Annals of Emergency Medicine 2008; 52(1):86–87.
Jimmink A, Caminada K, Hunfeld NG et al. Clinical toxicology of citalopram after acute
intoxication with the sole drug or in combination with other drugs: overview of 26
cases. Therapeutic Drug Monitoring 2008; 30(3):365–371.
Van Gorp F, Duffull S, Hackett LP, Isbister GK. Population pharmacokinetics and
pharmacodynamics of escitalopram in overdose and the effect of activated charcoal.
British Journal of Clinical Pharmacology 2011; 73:402–410.
Van Gorp F, Whyte IM, Isbister GK. Clinical and ECG effects of escitalopram overdose.
Annals of Emergency Medicine 2009: 54(3):404–408.
SPECIFIC TOXINS
3.72 STRYCHNINE
This heterocyclic ergot-type alkaloid is used as a rodenticide. Deliberate
self-poisoning by ingestion leads to the onset of generalised skeletal
muscle spasm within 30 minutes. Death from respiratory failure may
follow promptly. Paralysis, intubation and ventilation are life saving if
instituted before hypoxic neurological injury and multiple organ failure
occurs.
373
RISK ASSESSMENT
• Ingestion of as little as 30–100 mg by an adult is potentially lethal
(i.e. 1 g of 0.03% powder). Death can occur within 30 minutes.
TOXICOLOGY HANDBOOK
• Any deliberate ingestion is likely to be rapidly lethal without early
intervention.
• Sublethal doses lead to painful generalised muscle spasms and
stiffness precipitated by external stimuli.
• Children: an accidental taste is potentially lethal in a small child.
Toxic mechanism
Strychnine is a competitive glycine antagonist at brainstem and spinal postsynaptic
receptors. Glycine antagonism results in loss of normal descending inhibitory motor tone
and the onset of skeletal muscle spasm. Ventilatory failure occurs secondary to severe
muscular spasm.
Toxicokinetics
Strychnine is rapidly and completely absorbed following ingestion or inhalation. It is not
absorbed across intact skin. It has a large volume of distribution (13 L/kg). Up to 30% of
the dose is excreted unchanged in the urine. The remainder undergoes hepatic
microsomal (cytochrome P450) metabolism to inactive metabolites. The elimination
half-life is 10–16 hours.
CLINICAL FEATURES
• Onset of nausea, agitation, twitching and muscle spasms occurs
within minutes of ingestion.
• Generalised painful muscle spasms of all voluntary muscles
(risus sardonicus, opisthotonos) precipitated by any external
sensory stimulus rapidly progress, in severe cases, to
hyperthermia, rhabdomyolysis, lactic acidosis and respiratory
paralysis.
• Death is from ventilatory failure.
ERRNVPHGLFRVRUJ
• Loss of consciousness does not occur until secondary hypoxia
develops.
• If the acute phase is survived, myoglobinuria, renal failure and
hypoxic brain injury may complicate recovery.
• Muscle spasms and rigidity resolve within 24 hours if ventilation
and oxygenation are maintained.
INVESTIGATIONS
• Serum strychnine levels are not readily available and do not assist
management. Serum and urine levels are useful to confirm the
SPECIFIC TOXINS
diagnosis retrospectively, especially in forensic cases.

• EUC, CK, arterial blood gases, lactate and troponin.
MANAGEMENT
• Strychnine intoxication is a time-critical life-threatening
emergency.
374 include:
— Generalised muscle rigidity
37
— Respiratory failure.
4
• Prompt neuromuscular paralysis, intubation and ventilation are life

TOXICOLOGY HANDBOOK
saving.
• The patient is not unconscious and it is essential to ensure
adequate sedation.
• Mild intoxication, manifested by minor muscular twitching without
generalised spasm or respiratory compromise, is managed with IV
diazepam 5 mg every 5–10 minutes, titrated to achieve reduction
of spasm.
Decontamination
• Resuscitation takes priority over decontamination. Activated
charcoal is not indicated until the airway is secured.
Antidotes
• None available.
• Exposed patients who are clinically well without twitching or
muscle spasm at 4 hours post ingestion are not poisoned and are
cleared for medical discharge. Discharge should not occur at
night.
• Patients with objective evidence of strychnine intoxication (muscle
spasm or twitching) are managed in an intensive care unit. The
patient is clear for medical discharge once muscle spasm and
ERRNVPHGLFRVRUJ
rigidity have resolved, provided secondary complications of
spasm or hypoxia do not complicate clinical progress.
HANDY TIPS
• Patients with mild symptoms must be observed very carefully for
any signs of progression.
• Muscle spasm heralds the imminent onset of lethal muscle
rigidity – prepare for immediate paralysis, intubation and
ventilation.
PITFALLS
• Following deliberate self-poisoning, many patients do not reach
hospital alive.
SPECIFIC TOXINS
• Failure to institute prompt paralysis and intubation leading to
secondary complications, including hyperthermia, lactic acidosis,
rhabdomyolysis and hypoxic brain injury.
CONTROVERSY
• Forced diuresis, dialysis and urinary acidification have been
suggested, but are not recommended.
Presentations 375
Preparations available to the public contain 0.3% to 0.5% strychnine, but those used by
licensed exterminators may contain from 5% to 100% strychnine. Strychnine has been
added as an adulterant to street drugs such as amphetamines, cocaine and heroin.
TOXICOLOGY HANDBOOK
References
Edmunds M, Sheehan TM, Van’t Hoff W. Strychnine poisoning: clinical and toxicological
observations on a non-fatal case. Journal of Toxicology – Clinical Toxicology 1986;
24:245–255.
Makarovsky I, Markel G, Hoffman A et al. Strychnine: a killer from the past. Israeli
Medical Association Journal 2008; 10(2):142–145.
Palatnick W, Meatherall R, Sitar D et al. Toxicokinetics of acute strychnine poisoning.
Journal of Toxicology – Clinical Toxicology 1997; 35:617–620.
3.73 SULFONYLUREAS
Glibenclamide, Gliclazide, Glimepiride, Glipizide
Acute sulfonylurea overdose results in profound and prolonged
hypoglycaemia with onset usually within 8 hours of ingestion.
Hypoglycaemia can also develop at therapeutic doses, particularly in the
setting of acquired or preexisting renal dysfunction. Although initial
control of hypoglycaemia requires administration of concentrated
glucose solutions, early administration of the specific antidote,
octreotide, greatly simplifies subsequent management.
RISK ASSESSMENT
• Acute poisoning with sulfonylureas can result in profound
hypoglycaemia.
• Ingestion of just one tablet can produce hypoglycaemia in the
non-diabetic patient.
ERRNVPHGLFRVRUJ
• Sulfonylurea-induced hypoglycaemia is likely to be prolonged and
relapse is common following initial resolution that follows glucose
administration.
• Elderly patients are at particular risk of sulphonylurea-induced
hypoglycaemia, particularly those with impaired renal or hepatic
function, on multiple medications or frequently hospitalised.
• The hypoglycaemic response is more severe in the non-diabetic
patient.
• Onset of hypoglycaemia may be delayed up to 8 hours
following overdose (and even longer for modified-release
preparations).
• There is a wide variation in the duration of hypoglycaemic effect
depending on the preparation and dose. It may be several days
following large ingestions.
SPECIFIC TOXINS
• Children: ingestion of one tablet of any sulfonylurea is sufficient

to cause profound, potentially fatal, hypoglycaemia in a child.
Onset of hypoglycaemia is usually within 8 hours of the time of
ingestion but may be delayed up to 18 hours. The diagnosis
should be considered in any child who presents with
hypoglycaemia.
Toxic mechanism
376 The sulfonylureas are antidiabetic agents employed in the treatment of type 2 diabetes
37
mellitus. They stimulate endogenous insulin release from pancreatic beta cells through
6
the inhibition of K+ efflux. Overdose results in a hyperinsulinaemic state.

TOXICOLOGY HANDBOOK
Toxicokinetics
Sulfonylureas are rapidly and completely absorbed, with peak serum levels occurring
within 4–8 hours. Volumes of distribution are variable, but mostly small. They are
metabolised in the liver to active and inactive metabolites, which undergo renal
excretion. Elimination half-life varies between agents and is prolonged following
overdose.
CLINICAL FEATURES
• Autonomic and CNS manifestations of hypoglycaemia including:
— Sweating, tachycardia and confusion
— Altered mental status progressing to coma.
INVESTIGATIONS
• 12-lead ECG and paracetamol level
• Serial BGLs
• EUC
• Insulin levels may have some application if available
MANAGEMENT
• Administer concentrated IV glucose solutions as part of the initial
resuscitation of the already hypoglycaemic patient.
• Give adults 50 mL of 50% glucose as an IV bolus and children
5 mL/kg of 10% glucose IV.
ERRNVPHGLFRVRUJ
• Maintain euglycaemia by continued administration of concentrated
glucose solution until octreotide can be started.
• BGLs are monitored closely with bedside testing. They should be
checked at least hourly in the initial phase of treatment. This
frequency can be reduced in the stable patient on octreotide.
Decontamination
• Oral activated charcoal can be given where the patient presents
within 1 hour of acute overdose, providing mental state permits.
Activated charcoal could be considered up to 4 hours following
ingestion of a modified-release preparation.
SPECIFIC TOXINS
Antidote
• Octreotide is the specific antidote for sulfonylurea-induced
hyperinsulinaemia. Give adults a 50 microgram IV bolus followed
by 25 microgram/hour continuous infusion for at least 24 hours.
Give children 1 microgram/kg IV followed by 1 microgram/kg/hour
continuous infusion.
• See Chapter 4.19: Octreotide for further details.
DISPOSITION AND FOLLOW-UP 377
• All children with suspected sulfonylurea ingestion require
observation in hospital and monitoring of BGLs with bedside
testing for at least 18 hours.
TOXICOLOGY HANDBOOK
• All adult patients with definite or suspected sulfonylurea overdose
require observation for clinical features of hypoglycaemia and
monitoring of BGLs with bedside testing for at least 8 hours
(12 hours for modified-release preparations) from the time of the
overdose.
• Patients who remain asymptomatic, euglycaemic and clinically
well after an appropriate duration of observation may be
discharged.
• Symptomatic patients with hypoglycaemia treated with IV glucose
and octreotide are admitted. They are medically fit for discharge
once they maintain euglycaemia on a normal diet for at least 12
hours from the time of discontinuation of octreotide.
• The patient who develops hypoglycaemia on therapeutic doses of
a sulfonylurea requires admission for oral or IV glucose
administration, monitoring of the BGL, treatment of intercurrent
medical conditions and re-evaluation of diabetic therapy.
HANDY TIPS
• Early institution of octreotide therapy can completely avoid the
need for hypertonic dextrose infusions and central venous access.
— Octreotide may be administered SC if IV access is not readily
available.
• Do not ignore BGLs <4 mmol/L following sulfonylurea overdose. It
heralds the onset of profound hypoglycaemia.
• Documentation of hypoglycaemia is essential to confirm the
diagnosis of sulfonylurea overdose. Do not give concentrated
glucose or start octreotide until hypoglycaemia occurs.
ERRNVPHGLFRVRUJ
PITFALLS
• Recurrent administration of concentrated glucose boluses
stimulates endogenous insulin release and leads to rebound
hypoglycaemia. Supplies of octreotide should be procured as
soon as hypoglycaemia occurs in the setting of an acute overdose.
• Failure to admit a patient on therapeutic sulfonylurea who
presents with hypoglycaemia.
• Failure to observe, for a sufficient period, suspected paediatric
ingestions that present early while still euglycaemic.
CONTROVERSIES
• The observation period required for suspected ingestion of
modified-release preparations is unknown. Onset of
SPECIFIC TOXINS
hypoglycaemia could be delayed up to 48 hours.

• Optimal dose and route for administration of octreotide are yet to
be established. A safe approach is suggested in Chapter 4.19:
Octreotide.
• The role of insulin assays in monitoring response to octreotide
therapy.
Presentations
Glibenclamide 5 mg tablets (100)
378 Glibenclamide 1.25 mg/metformin 250 mg tablets (90)
37
Glibenclamide 2.5 mg/metformin 500 mg tablets (90)

8
Glibenclamide 5 mg/metformin 500 mg tablets (90)

Gliclazide 80 mg tablets (100)
TOXICOLOGY HANDBOOK
Gliclazide 30 mg modified-release tablets (100)

Gliclazide 60 mg modified-release tablets (60)
Glimepiride 1 mg tablets (30)
Glipizide 5 mg tablets (100)
References
Harrigan RA, Nathan MS, Beattie P. Oral agents for the treatment of type 2 diabetes
mellitus: pharmacology, toxicity and treatment. Annals of Emergency Medicine 2001;
38:68–78.
Lung DD, Olson KR. Hypoglycemia in paediatric sulfonylurea poisoning: an 8-year poison
center retrospective study. Pediatrics 2011; 127:e1558.
Spiller HA, Villalobos D, Krenzelok EP et al. Prospective multicenter study of sulfonylurea
ingestion in children. Journal of Pediatrics 1997; 131:141–146.
3.74 THEOPHYLLINE
Theophylline has an extremely narrow therapeutic index and both acute
overdose and chronic toxicity are potentially life threatening. Aggressive
supportive care and early accurate risk assessment to determine the
need for dialysis ensure a favourable outcome.
RISK ASSESSMENT
• All acute theophylline overdoses develop clinical features of
toxicity.
ERRNVPHGLFRVRUJ
• Ingestion of >50 mg/kg is expected to lead to life-threatening
toxicity, manifested by tachydysrhythmias and seizures (see
Table 3.74.1).

theophylline overdose
Dose Effect
5–10 mg/kg Therapeutic loading dose
>10 mg/kg Potential for toxicity
SPECIFIC TOXINS
>50 mg/kg Life-threatening toxicity
• Patients with chronic toxicity have a poor prognosis. This is

frequently compounded by failure to make the diagnosis or
appreciate the severity of the condition.
• Elderly patients with coexisting medical illnesses tolerate
theophylline toxicity poorly and are more likely to have a poor
outcome.
• Serum theophylline levels, when available, further refine risk 379
assessment (see Investigations below).
• Children: ingestion of even one 200-mg modified-release tablet
TOXICOLOGY HANDBOOK
will produce toxicity in a 10-kg child. Ingestion of multiple tablets
can be life threatening.
Toxic mechanism
Multiple toxic mechanisms have been proposed for theophylline, including competitive
antagonism of adenosine, altered intracellular calcium transport and inhibition of
phosphodiesterase leading to elevated intracellular cAMP concentrations.
Toxicokinetics
Theophylline is well absorbed after oral administration. Absorption is delayed with
modified-release preparations and peak levels may not occur until up to 15 hours
following ingestion. It is rapidly distributed with a small volume of distribution (0.5 L/ kg).
Metabolism is via the cytochrome P450 system to active and inactive metabolites.
Metabolism is variable and saturable. Elimination half-life may be greatly prolonged in
severe intoxication.
Aminophylline is a water-soluble complex of theophylline molecules suitable for

intravenous administration. It rapidly dissociates in vivo to release theophylline.
CLINICAL FEATURES
• Early manifestations of toxicity in acute overdose include anxiety,
vomiting, tremor and tachycardia.
• Severe poisoning is associated with:
— Cardiac dysrhythmias:
– Supraventricular tachycardia
– Atrial fibrillation and flutter
— Refractory hypotension
— Seizures
ERRNVPHGLFRVRUJ
— Metabolic abnormalities:
– Hypokalaemia (severe, refractory)
– Hypophosphataemia, hypomagnesaemia
– Hyperglycaemia
– Metabolic acidosis.
• Cardiac dysrhythmias and seizures occur late and indicate an
extremely poor prognosis.
• Chronic toxicity usually develops in elderly or infant patients and
generally presents with vomiting and tachycardia. The metabolic
effects are less pronounced than for acute overdose, but seizures
and dysrhythmias occur frequently and at lower serum
theophylline concentrations.
SPECIFIC TOXINS
INVESTIGATIONS
• Serial serum theophylline levels:
— Extremely useful in predicting the risk of life-threatening
toxicity
— In acute overdose, levels correlate well with clinical severity
380 (see Table 3.74.2) and are repeated every 2–4 hours until
falling
38
— Levels >330 micromol/L (60 mg/L) may be associated with

0
severe toxicity in elderly patients

TOXICOLOGY HANDBOOK
— In chronic intoxication, severe toxicity can occur at levels

>220 micromol/L (40 mg/L).
• UEC and acid–base status
TABLE 3.74.2 Correlation of serum levels and toxicity: Acute

theophylline overdose
Level (micromol/L) Level (mg/L) Toxicity
55–110 10–20 Therapeutic
110–220 20–40 Minor toxicity
220–440 40–80 Moderate toxicity
440–550 80–100 Severe toxicity
>550 >100 Usually fatal without

urgent intervention
MANAGEMENT
• Theophylline poisoning is a life-threatening emergency that is
and resuscitation.
ERRNVPHGLFRVRUJ
• Potential immediate life-threats include:
— Hypotension
— Seizures
— Ventricular and supraventricular tachycardia (SVT).
• Aggressive resuscitation and control of seizures is required in
severe theophylline toxicity. The patient who presents with
established severe toxicity has an extremely poor prognosis.
Supportive care measures do not ensure survival and are
instituted in an effort to allow sufficient time for definitive
treatment with haemodialysis.
• Hypotension usually responds to fluid administration, although a
noradrenaline infusion may be needed in resistant cases. Give
10–20 mL/kg of IV crystalloid solution as an initial response (see
Chapter 2.5: Hypotension).
SPECIFIC TOXINS
• Treat seizures with benzodiazepines, as outlined in Chapter 2.6:
Seizures.
• Supraventricular tachycardia is controlled with beta-blockade
using carefully titrated doses of propranolol or metoprolol, or an
esmolol infusion. Beware bronchospasm in susceptible individuals
(asthmatics). Administer propranolol 0.5–1 mg or metoprolol 5 mg
(0.1 mg/kg in children) by slow IV injection and repeat after 5
minutes if response inadequate. An esmolol infusion is prepared
at a concentration of 10 mg/mL in 5% dextrose and commenced 381
at a rate of 0.05 mg/kg/minute (20 mL/hour in a 70-kg adult) and
titrated to response.
• Metabolic disturbances do not generally require specific therapy,
TOXICOLOGY HANDBOOK
although severe hypokalaemia, if present, should be corrected
with potassium supplementation.
Decontamination
• Oral activated charcoal is indicated following acute overdose even
if presentation is delayed. Aggressive control of vomiting with
antiemetics, such as ondansetron 4 mg IV or tropisetron 2 mg IV,
is usually necessary for success in the unintubated patient.
• Haemodialysis is the definitive life-saving intervention in severe
theophylline poisoning and highly effective in achieving good
clinical outcome if commenced early.
• Arrangements for urgent haemodialysis are made as soon as
potentially life-threatening theophylline toxicity is anticipated.
Commonly accepted indications are:
— Serum theophylline >550 micromol/L (100 mg/L) in the setting
of acute overdose
— Serum theophylline >330 micromol/L (60 mg/L) in the setting
of chronic toxicity
— Clinical manifestations of severe toxicity – dysrhythmia,
hypotension or seizures.
• Multiple-dose activated charcoal enhances the elimination of
theophylline, but use of this modality delays effective treatment
with haemodialysis.
Antidotes
• None available.
ERRNVPHGLFRVRUJ
• Patients who have acutely ingested theophylline syrup and are
asymptomatic at 6 hours may be medically cleared.
• Overdose of modified-release tablets requires observation
for 12 hours although serial levels may hasten medical
clearance.
• All symptomatic patients are admitted to a monitored environment
for close observation and serial theophylline levels. If the initial
risk assessment, subsequent clinical progress or theophylline
levels indicate potential for severe toxicity, retrieval to a facility
with an intensive care unit capable of emergency haemodialysis
is undertaken as soon as possible, preferably before clinical
deterioration.
SPECIFIC TOXINS
HANDY TIPS
• Patients at risk of death should be identified and dialysed before
clinical deterioration.
• Most theophylline overdoses are of modified-release preparations
and clinical deterioration is delayed many hours.
• Cardiac dysrhythmias (including SVT), hypotension or seizures
are predictive of poor outcome in both acute and chronic
382 toxicity. Any one of these clinical features mandates urgent
haemodialysis.
38
2
PITFALLS
TOXICOLOGY HANDBOOK
• Failure to identify high-risk cases early based on dosing history.

This delays arrangements for haemodialysis until the patient is
clinically unstable.
• Failure to closely observe and follow theophylline levels.
CONTROVERSIES
• Beta-blocker use in asthmatic patients with theophylline toxicity. If
beta-blockers are used, short-acting, cardioselective agents such
as esmolol given by titrated infusion are preferred.
• Charcoal haemoperfusion is described as the modality of choice
for enhancing theophylline elimination. However, the technique is
not widely available and standard haemodialysis is effective and
usually able to be implemented more quickly.
Presentations
Aminophylline 25 mg/mL ampoules (10 mL)
Theophylline 200 mg modified-release tablets (100)
Theophylline 5.32 mg/mL oral liquid (500 mL)
References
Minton NA, Henry JA. Treatment of theophylline overdose. American Journal of
Shannon M. Life-threatening events after theophylline overdose: a 10-year prospective
analysis. Archives of Internal Medicine 1999; 159:989–994.
ERRNVPHGLFRVRUJ
3.75 THYROXINE
Overdose of thyroxine is rarely sufficient to produce significant
symptoms of hyperthyroidism. When these do occur, they are mild,
delayed in onset and may last up to 2 weeks. They can usually be
successfully managed in the outpatient setting.
RISK ASSESSMENT
• The majority of patients with acute thyroxine overdose remain
asymptomatic or experience only mild-to-moderate symptoms of
hyperthyroidism some 2–7 days later.
• Symptoms are not expected unless >10 mg of thyroxine is
SPECIFIC TOXINS
ingested.
• The elderly and patients with cardiovascular co-morbidities are at
increased risk of complications should hyperthyroid symptoms
occur.
• Severe toxicity is more likely to occur following chronic abuse of
thyroid hormones.
• Children: ingestion of up to 5 mg is associated with minimal
symptoms. Severe thyrotoxicosis has not been reported after
unintentional paediatric ingestion of thyroxine. 383
Toxic mechanism
Thyroxine (T4) is converted to tri-iodothyronine (T3) in the liver and kidney. T3 binds to the
TOXICOLOGY HANDBOOK
nucleus and influences multiple metabolic processes (cardiovascular, metabolic, growth
and development).
Toxicokinetics
Oral bioavailability is high (80%) with a maximal absorption at 2 hours post ingestion.
Onset of the hormonal effect is delayed and maximal effects are not attained until 1–3
weeks. Thyroxine is extensively distributed and bound completely to proteins. The
elimination half-life is 6–7 days after therapeutic dosing and is shortened to a mean of 3
days following overdose.
CLINICAL FEATURES
• Following acute ingestion, most patients remain
asymptomatic.
• Where symptoms do develop, they are not usually apparent
until >24 hours following the ingestion but may then last more
than 1 week.
• Signs and symptoms when they do occur are those of adrenergic
stimulation and include fever, agitation, sweating, tachycardia,
hypertension, headache, diarrhoea and vomiting.
• Chronic ingestion of excessive thyroxine causes severe illness
characterised by angina pectoris, myocardial infarction,
myocarditis, ventricular and atrial dysrhythmias, left ventricular
hypertrophy, thyrotoxicosis and thyroid storm.
INVESTIGATIONS
ERRNVPHGLFRVRUJ
• Thyroid function tests after overdose usually show marked
elevation of thyroxine concentration that is without clinical
correlate. They do not assist in management following either
accidental paediatric ingestion or deliberate self-poisoning and
are not indicated.
MANAGEMENT
• Resuscitation measures are rarely required.
• Beta-blockers rapidly control the sympathomimetic symptoms
SPECIFIC TOXINS
of thyroid excess. In symptomatic patients with no

contraindications to beta-blockade, administer oral propranolol
10–40 mg (0.2–0.5 mg/kg in children) every 6 hours.
• If beta-blockers are contraindicated, calcium channel blockers are
a suitable alternative. Administer diltiazem 60–180 mg (1–3 mg/kg
in children) every 8 hours.
• Close clinical and physiological monitoring is indicated for
patients with severe symptoms.
384 Decontamination
• Give oral activated charcoal 50 g to cooperative patients who
38
4
present within 1 hour of ingesting >10 mg of thyroxine.

• Oral activated charcoal is not indicated in children following
TOXICOLOGY HANDBOOK
unintentional ingestion.
Antidotes
• None available.
• Children suspected of ingesting up to 5 mg of thyroxine may be
observed at home provided they remain asymptomatic.
• Adult patients with acute deliberate self-poisoning rarely
require immediate management. Disposition occurs as
dictated by the medical and psychiatric condition, with advice
to report symptoms of thyroid toxicity. If these occur, supportive
therapy with beta-blockers is indicated, usually for a period of
1 week. Thyroxine may be restarted after a week if indicated.
HANDY TIP
• Many patients remain asymptomatic. If symptoms occur, onset is
usually delayed >24 hours post ingestion.
PITFALLS
• Unnecessary admission for prolonged medical observation.
• Failure to anticipate or recognise the delayed onset of symptoms
following large overdoses.
ERRNVPHGLFRVRUJ
Presentations
Thyroxine 50 microgram tablets (200)
References
Lewander WJ, Lacouture PG, Silva JE et al. Acute thyroxine ingestion in pediatric
patients. Pediatrics 1989; 84:262–265.
Litovitz TL, White JD. Levothyroxine ingestions in children: an analysis of 78 cases.
American Journal of Emergency Medicine 1985; 3:297–300.
Shilo L, Kovatz S, Hadari R et al. Massive thyroid hormone overdose: clinical
manifestations and management. Israeli Medical Association Journal 2002; 4:
298–299.
SPECIFIC TOXINS
Tunget CL, Clark RF, Turchen SG et al. Raising the decontamination level for thyroid
hormone ingestions. American Journal of Emergency Medicine 1995; 13:9–13.
3.76 TRAMADOL
Tramadol is a centrally acting synthetic opioid analgesic. Most available
formulations are sustained release and, in overdose, frequently cause
delayed-onset seizures. Tramadol overdose may also cause mild 385
sedation and respiratory depression.
RISK ASSESSMENT
TOXICOLOGY HANDBOOK
• Opioid effects (sedation and respiratory depression) are usually
mild and rarely require intervention.
• The major potential risk is seizures and these are usually delayed
in onset (>6 hours). Seizures should be anticipated in patients
who ingest >1.5 g tramadol.
• Serotonin syndrome may develop if there is co-ingestion of other
serotonergically active agents.
• Children: CNS depression and seizures can occur with ingestion
of >10 mg/kg.
Toxic mechanism
Tramadol is a weak partial agonist at µ opioid receptors. It also inhibits serotonin and
noradrenaline reuptake in the CNS. The toxic effects in overdose seem to be primarily a
result of the inhibition of CNS serotonin and noradrenaline reuptake.
Toxicokinetics
Tramadol is well absorbed orally and peak levels occur at 1–3 hours after ingestion of
standard preparations and 2–12 hours after ingestion of sustained-release preparations.
Peak levels may be further delayed after overdose. The volume of distribution is 2–3 L/kg.
It is extensively metabolised in the liver and one of the metabolites, O-desmethyltramadol,
is pharmacologically active. Elimination is in the urine with elimination half-lives of 5–7
hours for the parent drug and 6–8 hours for the active metabolite.
CLINICAL FEATURES
• Opioid agonist effects are not prominent and consist of mild
sedation, mild respiratory depression and miosis.
• Coma requiring intubation is unusual except in the presence of
co-ingestants, especially ethanol or benzodiazepines.
ERRNVPHGLFRVRUJ
• Serotonergic and noradrenergic effects are more prominent and
may include tachycardia, agitation, mydriasis and seizures.
• Seizures are the most serious clinical effect. They are delayed in
onset (usually >6 hours after overdose of the sustained-release
preparation), of short duration and easily controlled with
benzodiazepines.
• Serotonin syndrome may develop, especially if there is
co-ingestion of other serotonergically active drugs (see Chapter
2.8: Serotonin syndrome).
INVESTIGATIONS
SPECIFIC TOXINS

• Specific investigations are only indicated to diagnose and assess
secondary complications.
MANAGEMENT
386 in Chapter 1.2: Resuscitation.
38
6

• Seizures are treated with titrated doses of IV benzodiazepines, as
TOXICOLOGY HANDBOOK
outlined in Chapter 2.6: Seizures.

• Increasing agitation, tachycardia, tremor and myoclonic jerks
herald onset of seizures and these symptoms are controlled with
titrated IV doses of diazepam: give 2.5–5 mg every 2–5 minutes
until gentle sedation is achieved and the heart rate falls towards
100 beats/minute.
• Serotonin syndrome, if it develops, should be identified and
managed as described in Chapter 2.8: Serotonin syndrome.
Decontamination
• Administration of oral activated charcoal 50 g is considered in
the patient who is alert and cooperative and presents within
2 hours of ingestion of >1.5 g of a sustained-release tramadol
preparation.
• The potential for seizures must be considered when making a
risk–benefit analysis of the value of administering activated
charcoal.
• In the patient who is intubated, activated charcoal may be safely
administered via a nasogastric tube.
Antidotes
• Naloxone may reverse CNS and respiratory depression secondary
to µ opioid agonist activity (see Chapter 4.18: Naloxone).
ERRNVPHGLFRVRUJ
However, this is rarely a clinically significant problem with pure
tramadol overdose and naloxone is rarely useful.

• Children suspected of ingesting >10 mg/kg of sustained-release
tramadol must be assessed and observed in hospital for at least
12 hours. Discharge should not occur at night.
• Because of the risk of seizures, all adult patients who have ingested
>1.5 g of sustained-release tramadol must be observed with IV
access in place for a minimum of 12 hours and until symptom free.
• Patients who are significantly sedated or require benzodiazepine
administration for seizure or symptom control should be admitted
for continued observation and supportive care until symptom free.
SPECIFIC TOXINS
• Patients who require intubation for coma or severe serotonin
syndrome are admitted to intensive care.
HANDY TIP
• Prophylactic administration of intravenous benzodiazepines to
patients with clinical features of toxicity such as agitation,
tachycardia, tremor or myoclonic jerking will usually prevent
seizures.
387
PITFALLS
• Failure to anticipate and prepare for delayed symptoms or seizures.
•
TOXICOLOGY HANDBOOK
Administration of activated charcoal shortly before onset of
seizures.
Presentations
Tramadol hydrochloride 50 mg capsules (20)
Tramadol hydrochloride 50 mg sustained-release tablets (20)
Tramadol hydrochloride 100 mg sustained-release tablets (10, 20)
Tramadol hydrochloride 200 mg sustained-release tablets (10, 20)
Tramadol hydrochloride 100 mg/1 mL oral liquid (10 mL)
Tramadol 50 mg/mL ampoules (2 mL)
Tramadol 37.5 mg/paracetamol 325 mg (20, 50)
References
Persson H, Sjöberg G. Acute toxicity of tramadol: analyses of 287 cases (abstract).
Clinical Toxicology 2008; 46:398.
Sachdeva DK, Stadnyk JM. Are one or two dangerous? Opioid exposure in toddlers.
Shadnia S, Soltaninejad K, Heyardi K et al. Tramadol intoxication: a review of 114 cases.
Human and Experimental Toxicology 2008; 27:201–205.
Spiller HA, Gorman SE, Villalobos D et al. Prospective multicenter evaluation of tramadol
exposure. Journal of Toxicology – Clinical Toxicology 1997; 35(4):361–364.
3.77 TRICYCLIC ANTIDEPRESSANTS (TCAs)

Amitriptyline, Clomipramine, Dothiepin, Doxepin, Imipramine,
Nortriptyline, Trimipramine
ERRNVPHGLFRVRUJ
Tricyclic antidepressant (TCA) poisoning remains a major cause of
morbidity and mortality. Deliberate self-poisoning may lead to the rapid
onset of CNS and cardiovascular toxicity. Prompt intubation,
hyperventilation and sodium bicarbonate administration at the first
evidence of severe toxicity are life saving.
RISK ASSESSMENT
• Ingestion of >10 mg/kg is potentially life threatening (see Table
3.77.1).
• Onset of severe toxicity usually occurs within 2 hours of ingestion.
• Seizures and myoclonus are more common with dothiepin.
• Children: ingestion of >10 mg/kg of amitriptyline, dothiepin,
doxepin or trimipramine tablets is potentially lethal in a 10-kg
SPECIFIC TOXINS
toddler. Any child who is suspected of ingesting >5 mg/kg is

referred to hospital for 6 hours of observation.
TABLE 3.77.1 Dose-related risk assessments: Tricyclic

antidepressants
Dose Effect
388 <5 mg/kg Minimal symptoms

38
5–10 mg/kg Drowsiness and mild anticholinergic effects

8
Major toxicity not expected

TOXICOLOGY HANDBOOK
>10 mg/kg Potential for all major effects (coma,

hypotension, seizures, cardiac dysrhythmias)
to occur within 2–4 hours of ingestion
Anticholinergic effects likely but often masked
by coma
>30 mg/kg Severe toxicity with pH-dependent cardiotoxicity

and coma expected to last >24 hours
Toxic mechanism
TCAs are noradrenaline and serotonin reuptake inhibitors and GABAA receptor-blockers.
Myocardial toxicity is chiefly due to blockade of inactivated fast sodium channels. Other
toxic effects are mediated by blockade at muscarinic (M1), histaminic (H1) and peripheral
post-synaptic α1-adrenergic receptors. TCAs cause reversible inhibition of potassium
channels and direct myocardial depression unrelated to conduction abnormalities.
Toxicokinetics
TCAs are rapidly absorbed following oral administration, with peak levels occurring within
2 hours. TCAs are highly bound to plasma and tissue proteins and have large volumes of
distribution (5–20 L/kg). TCAs undergo hepatic metabolism by oxidation (cytochrome
P450 2D6) to active metabolites. Some enterohepatic circulation occurs.
CLINICAL FEATURES
Severe toxicity is characterised by rapid deterioration in clinical status
within 1–2 hours of ingestion. Patients may present alert and
orientated, only to rapidly develop coma, seizures, hypotension and
cardiac dysrhythmias.
ERRNVPHGLFRVRUJ
— Sedation and coma usually precede cardiovascular signs
— Seizures
— Delirium secondary to anticholinergic effects is often obscured
by coma
• Cardiovascular
— Sinus tachycardia and mild elevation of blood pressure
— Hypotension due to alpha blocking effects and impaired
contractility
— Broad-complex tachydysrhythmias
— Broad-complex bradycardia occurs pre-arrest
• Anticholinergic effects
— Can occur on presentation or may be delayed and prolonged
— Agitation, restlessness, delirium
SPECIFIC TOXINS
— Mydriasis
— Dry, warm, flushed skin
— Tachycardia, urinary retention, ileus
— Myoclonic jerks
INVESTIGATIONS
389
• Serial ECGs
— Vital tool in the management of TCA intoxication (see Chapter
TOXICOLOGY HANDBOOK
2.20: The 12-lead ECG in Toxicology).
— Diagnostic features include:
– Prolongation of QRS interval
– Large terminal R wave in aVR
– Increased R/S ratio (>0.7) in aVR
– QT prolongation is also noted secondary to potassium
channel blockade
– See Appendix 2 for examples of ECGs in TCA poisoning.
— QRS widening reflects degree of fast sodium channel blockade.
— QRS >100 ms is predictive of seizures.
— QRS >160 ms is predictive of ventricular tachycardia.
MANAGEMENT
• Acute TCA poisoning is a potentially life-threatening emergency
and resuscitation.
• Close clinical and physiological monitoring is mandatory for at
least 6 hours post ingestion.
• Cardiac monitoring is continued until resolution of toxicity.
include:
— Coma
— Respiratory acidosis
— Seizures
— Cardiac arrest.
ERRNVPHGLFRVRUJ
• At the onset of CNS depression (e.g. GCS <12), prompt intubation
and hyperventilation are indicated.
• Ventricular dysrhythmias
— Cardioversion and defibrillation are unlikely to be effective.
— Administer sodium bicarbonate 100 mmol (2 mmol/kg) IV
repeated every 1–2 minutes until restoration of perfusing
rhythm (see Chapter 4.24: Sodium bicarbonate for further
details).
— Lignocaine (1.5 mg/kg) IV is third-line therapy when pH is
established at >7.5.
— Type Ia antidysrhythmic agents (e.g. procainamide),
amiodarone and beta-blockers are contraindicated.
• Hypotension is treated with IV crystalloid solutions (10–20 mL/
kg), sodium bicarbonate 100 mmol (2 mmol/kg) and adrenaline or
SPECIFIC TOXINS
noradrenaline infusion (see Chapter 2.5: Hypotension).

• Seizures are managed with benzodiazepines, as outlined in
• Intubated patients are hyperventilated to maintain serum pH
7.50–7.55.
Decontamination
390
• Activated charcoal is not indicated for ingestions <10 mg/kg, as
39
good outcome is expected with supportive care.

0
• In patients with significant ingestions, activated charcoal is

TOXICOLOGY HANDBOOK
indicated, but should never be administered until after the airway

is secured by endotracheal intubation and only after dealing with
all resuscitation priorities.
Antidotes
• Sodium bicarbonate as above and see Chapter 4.24: Sodium
bicarbonate.

• Patients who are clinically well, with normal 12-lead ECG (or static
preexisting changes), normal mental status, no hypotension and
no seizures at 6 hours post ingestion do not require further
cardiac monitoring or observation and are medically fit for
discharge.
• Patients with minor abnormalities of mental status or 12-lead ECG
at 6 hours post ingestion require ongoing careful observation,
ECG monitoring and reassessment of 12-lead ECGs, until there is
clear evidence of clinical improvement.
• Patients requiring intubation and ventilation are admitted to an
HANDY TIPS
• Resuscitation efforts do not cease until the patient has been
intubated, and treated with sodium bicarbonate and
hyperventilation to achieve a serum pH of 7.50–7.55. Numerous
ERRNVPHGLFRVRUJ
reports describe survival with good neurological outcome
following prolonged cardiac arrest and CPR (up to hours).
• Onset of coma may be abrupt and followed by rapid decline and
arrest if rapid intubation, hyperventilation and sodium bicarbonate
are not undertaken. These interventions are sufficient to ensure
survival of all patients who arrive alive at hospital and most of
those who arrive shortly after arrest.
PITFALL
• Insufficient doses of sodium bicarbonate when attempting
resuscitation of severe TCA poisoning.
CONTROVERSIES
•
SPECIFIC TOXINS
Value and indications for prophylactic serum alkalinisation.
• Relative efficacy of hyperventilation versus sodium bicarbonate.
• Efficacy of hypertonic saline.
Presentations
Amitriptyline hydrochloride 10 mg tablets (50)
Clomipramine hydrochloride 25 mg tablets (50)
Dothiepin hydrochloride 25 mg capsules (50)
Dothiepin hydrochloride 75 mg tablets (30) 391
Doxepin hydrochloride 10 mg capsules (50)
Doxepin hydrochloride 25 mg capsules (50)
Doxepin hydrochloride 50 mg tablets (50)
TOXICOLOGY HANDBOOK
Imipramine hydrochloride 10 mg tablets (50)
Imipramine hydrochloride 25 mg tablets (50)
Nortriptyline hydrochloride 10 mg tablets (50)
Nortriptyline hydrochloride 25 mg tablets (50)
Trimipramine 25 mg tablets (50)
Trimipramine 50 mg capsules (50)
References
Bateman ND. Tricyclic antidepressant poisoning: central nervous system effects and
management. Toxicological Reviews 2005; 24(3):181–186.
Bradberry SM, Thanacoody HKR, Watt BE et al. Management of the cardiovascular
complications of tricyclic antidepressant toxicity: role of sodium bicarbonate.
Heard K, Cain BS, Dart RC et al. Tricyclic antidepressants directly depress human
myocardial mechanical function independent of effects on the conduction system.
Academic Emergency Medicine 2001; 8(12):1122–1127.
Liebelt EL, Francis PD, Woolf AD. ECG lead aVR versus QRS interval in predicting
seizures and arrhythmias in acute tricyclic antidepressant toxicity. Annals of
3.78 VALPROIC ACID (SODIUM VALPROATE)

Most valproate overdoses result in CNS depression and are managed
successfully with supportive care. Large overdoses can cause multi-
system organ failure and death. Death is preventable with early
haemodialysis. Chronic valproate therapy is associated with life-
threatening idiosyncratic toxicities including hyperammonaemia and
hepatotoxicity.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• Dose-dependent CNS depression may be delayed up to 12 hours
(see Table 3.78.1).
• Increasingly severe multi-system organ effects occur as doses
rise above 400 mg/kg.
• Ingestion of >1 g/kg is potentially lethal.
TABLE 3.78.1 Dose-related risk assessment: Valproic acid
Dose Effect
<200 mg/kg Asymptomatic, or mild drowsiness and ataxia

SPECIFIC TOXINS
only
200–400 mg/kg Variable CNS depression; airway control

rarely required
400–1000 mg/kg Significant CNS depression likely

Coma requiring intubation may be delayed up
to 12 hours after ingestion
As doses increase within this range, more
392 severe multi-system toxicity is observed
39
>1000 mg/kg Potentially lethal with profound prolonged

2
coma and multiple organ toxicity,

TOXICOLOGY HANDBOOK
including cerebral oedema, hypotension,

lactic acidosis, hypoglycaemia,
hyperammonaemia, hypernatraemia,
hypocalcaemia and bone marrow
suppression
• Children: unintentional ingestions of <200 mg/kg may be

observed at home. Referral to hospital for assessment is indicated
if more than this amount may have been ingested, or if symptoms
develop.
Toxic mechanism
Valproate increases levels of gamma-aminobutyric acid (GABA), a central inhibitory
neurotransmitter. In large doses, it interferes with numerous mitochondrial metabolic
pathways.
Toxicokinetics
Valproate is usually well absorbed following oral administration, but absorption may be
slow and erratic following overdose. Peak levels may be delayed up to 18 hours.
Valproate is highly protein bound and has a very small volume of distribution (0.1–0.2 L/
kg). Valproate undergoes hepatic metabolism to produce multiple active metabolites.
CLINICAL FEATURES
• The patient frequently presents relatively asymptomatic, even after
large ingestions.
• Progressive deterioration in conscious state is paralleled closely
by rising serum levels (see below).
ERRNVPHGLFRVRUJ
• Following large ingestions, coma is accompanied by:
— Metabolic abnormalities (anion gap metabolic acidosis,
hypoglycaemia, hypernatraemia, hypocalcaemia and
hyperammonaemia)
— Other evidence of systemic toxicity, including hypotension,
renal impairment and bone marrow depression.
• In very severe poisoning, cerebral oedema, prolonged coma,
cardiovascular instability and death occur.
• In severe poisoning, coma and manifestations of toxicity may
persist for several days after serum valproate levels return to
normal.
INVESTIGATIONS
SPECIFIC TOXINS
• Serial valproate levels: confirm poisoning; refine risk assessment
and guide therapy. Serum valproate levels correlate well with the
degree of CNS depression and the risk of developing multi-
system toxicity (see Table 3.78.2).
• If CNS depression develops, or ingestion >400 mg/kg is
suspected, serum valproate levels are repeated every 4–6 hours 393
until they decrease.
• In the comatose patient, valproate levels are essential to
determining the risk of life-threatening multi-system valproate
TOXICOLOGY HANDBOOK
toxicity and need for haemodialysis.
• Serial EUC, acid–base status and full blood counts are followed
in all comatose patients to detect and manage multi-system
toxicity.
TABLE 3.78.2 Correlation of clinical effects with serum

valproate level
Serum valproate Clinical effects
<3500 micromol/L Not usually associated with multiple

(<500 mg/L) organ effects
>3500 micromol/L Usually manifest coma and may have

(>500 mg/L) other organ effects
>7000 micromol/L Frequently develop life-threatening

(>1000 mg/L) multiple organ effects
>14 000 micromol/L Death expected without urgent

(>2000 mg/L) haemodialysis
MANAGEMENT
• All patients are managed in an area equipped for cardiopulmonary
ERRNVPHGLFRVRUJ
Decontamination
• Oral activated charcoal is not indicated in patients who have
ingested <400 mg/kg.
• In larger ingestions activated charcoal 50 g is administered via the
nasogastric tube after securing the airway with endotracheal
intubation, as outlined in Chapter 1.6: Gastrointestinal
SPECIFIC TOXINS
decontamination.
• A repeat dose of activated charcoal at 3–4 hours may reduce
absorption and peak serum levels, and is recommended in
intubated patients with preserved bowel sounds and rising
valproate levels.
• Haemodialysis removes valproic acid efficiently and is indicated
whenever life-threatening systemic toxicity is anticipated:
394 — Ingestion of >1000 mg/kg with serum level >7000 micromol/L
39
(1000 mg/L)
4
— Serum level >10 400 micromol/L (1500 mg/L) at any time

— Severe valproic acid poisoning with lactic acidosis or
TOXICOLOGY HANDBOOK
cardiovascular instability.
• Haemodialysis is ideally performed before multi-system organ
dysfunction is evident.
Antidotes
• None available.
• Patients who ingest <200 mg/kg are observed in a ward
environment for 8 hours. They are fit for medical discharge after
that time as soon as they are alert and ambulant.
• Those who ingest larger amounts are observed closely for
deteriorating conscious state. If coma develops, the patient is
intubated and ventilated and admitted to an intensive care unit.
HANDY TIPS
• After large ingestions, absorption is slow and erratic. Coma may
be delayed for up to 8–12 hours.
• Consider valproic acid overdose in any patient with unexplained
coma, particularly where there is hypernatraemia, hypocalcaemia
or lactic acidosis.
• The valproate level taken on arrival may be within normal
therapeutic range, even following a life-threatening ingestion—
always repeat the level if there is any decline in the level of
consciousness.
• Urgent valproate levels are essential in the comatose patient to
stratify risk and the need for haemodialysis.
ERRNVPHGLFRVRUJ
• Continuous veno-venous haemofiltration and haemodiafiltration
do not appear to be as effective as haemodialysis in removing
valproate, but are acceptable alternatives if more readily
available.
PITFALL
• Falsely low levels have been reported from laboratory equipment
not calibrated for levels exceeding 3000 micromol/L (450 mg/L).
CONTROVERSIES
• The benefit of haemodialysis has not been validated with
controlled trials and the indications for this intervention remain
controversial.
SPECIFIC TOXINS
• Whole bowel irrigation (WBI) has been advocated in large valproic
acid ingestions (>1 g/kg) if the patient presents within 4 hours.
Progressive CNS depression renders the procedure difficult and
hazardous. In the intubated patient, WBI may not be feasible;
early haemodialysis is highly effective and a more appropriate
intervention in this life-threatening situation
• Carnitine has been suggested as an antidote for valproate-
induced mitochondrial effects. These recommendations are based
on case reports and extrapolation from treatment of children with
selected inborn errors of metabolism. Carnitine is not 395
recommended at this time.
TOXICOLOGY HANDBOOK
Presentations
Sodium valproate 100 mg tablets (100)
Sodium valproate 200 mg enteric-coated tablets (100, 200)
Sodium valproate 500 mg enteric-coated tablets (100, 200)
Sodium valproate 40 mg/mL oral liquid (300 mL, 600 mL)
Sodium valproate 400 mg, injectable (powder + solvent) (4 mL)
References
Isbister GK, Balit CR, Whyte IM et al. Valproate overdose: a comparative cohort study of
self-poisonings. British Journal of Clinical Pharmacology 2003; 55:398–404.
Spiller HA, Krenzelok EP, Klein-Schwartz W et al. Multicenter case series of valproic acid
ingestion: serum concentrations and toxicity. Clinical Toxicology 2000;
38(7):755–760.
Sztajnkrycer MD. Valproic acid toxicity: overview and management. Journal of Toxicology
– Clinical Toxicology 2002; 40(6):789–801.
Thanacoody RH. Extracorporeal elimination in acute valproic acid poisoning. Clinical
Toxicology 2009; 47(7):609–616.
3.79 VENLAFAXINE AND DESVENLAFAXINE

Venlafaxine and desvenlafaxine are potent selective serotonin and
noradrenaline reuptake inhibitors. Venlafaxine overdose is potentially life
threatening; it frequently causes seizures and, in very large ingestions,
cardiovascular toxicity. Supportive care and adequate benzodiazepine
sedation usually ensure a good outcome. There is less clinical
experience with desvenlafaxine, but it is likely that the clinical features of
overdose are similar to those of venlafaxine.
ERRNVPHGLFRVRUJ
RISK ASSESSMENT
• 14% of patients have seizures but the incidence is dose
dependent (see Table 3.79.1).
• Onset of seizures may be delayed up to 16 hours following
overdose.
• Preexistent seizure disorder may increase the probability of
seizures.
• There is a high risk of serotonin syndrome if other serotonergic
agents are co-ingested (see Table 2.8.2), irrespective of the dose
of venlafaxine.
• Massive ingestion (>7 g) is associated with cardiovascular
effects.
SPECIFIC TOXINS
TABLE 3.79.1 Dose-related risk assessment: Venlafaxine
Dose Effect
<1.5 g Risk of seizures <5%
<3 g Risk of seizures 10%

396 >3 g Risk of seizures >30%
39
6
>4.5 g Risk of seizures approaches 100%

Hypotension
TOXICOLOGY HANDBOOK
Minor QRS and QT prolongation on 12-lead ECG
>7 g Hypotension
Left ventricular dysfunction
• Children: accidental ingestion of <12.5 mg/kg is not associated

with significant symptoms. Referral to hospital is not required
unless symptoms occur.
Toxic mechanism
Venlafaxine and its metabolite O-desmethylvenlafaxine (desvenlafaxine) are potent
serotonin and noradrenaline reuptake inhibitors (SNRIs). They also exhibit rate-dependent
sodium channel blocking activity. They have only weak dopamine reuptake activity and
no activity at muscarinic, histamine (H1) or α1-adrenegic receptors. They do not inhibit
monoamine oxidase (MAO).
Toxicokinetics
Venlafaxine is well absorbed and undergoes extensive first-pass metabolism, resulting in
bioavailability of only 50%. All currently available preparations are controlled-release and
peak plasma levels occur at 6–8 hours. The volume of distribution of venlafaxine is
5–7 L/kg. The apparent elimination half-life following therapeutic doses of modified-
release preparations is 15 hours.
Desvenlafaxine is also well absorbed, but does not undergo extensive first-pass
metabolism and has a bioavailability of 80%. The volume of distribution is 3–4 L/kg. Up
to 45% of an ingested dose is excreted unchanged in the urine, with the rest
predominantly undergoing glucuronide conjugation. The elimination half-life is
approximately 11 hours.
ERRNVPHGLFRVRUJ
CLINICAL FEATURES
• Onset of significant clinical features of toxicity may be delayed up
to 6–12 hours following overdose.
• Dysphoria, anxiety, mydriasis, sweating, tremor, clonus,
tachycardia (up to 160 beats/minute) and hypertension are
common, and may herald the onset of seizures.
• Seizures are generalised, short duration and self-limiting. The first
seizure may be delayed up to 16 hours.
• Coma is not a feature of venlafaxine intoxication.
• Although some clinical features of intoxication may be
serotonergic in origin, severe serotonin syndrome develops only
where there is co-ingestion of other serotonergically active drugs,
especially MAO inhibitors.
SPECIFIC TOXINS
• Hypotension occurs following very large ingestions and, again,
onset may be delayed up to 12 hours.
• Large venlafaxine overdoses may cause diffuse, severe left
ventricular dysfunction.
• Minor dose-dependent QRS and QT prolongation may occur with
venlafaxine intoxication but is unlikely to be associated with
dysrhythmias, except perhaps following massive overdose.
• Rhabdomyolysis and hypoglycaemia, occasionally severe, are
reported infrequently following large overdose of venlafaxine.
397
• Venlafaxine intoxication usually resolves within 24 hours.
INVESTIGATIONS
TOXICOLOGY HANDBOOK
• Serial ECGs
— Perform a 12-lead ECG on all patients at presentation and
6 hours post ingestion.
• Creatine kinase
— Detect and monitor rhabdomyolysis.
MANAGEMENT
• Venlafaxine overdose is a life-threatening emergency and
and resuscitation. The principal threat to life is seizures.
• Increasing agitation, tachycardia and tremor herald onset of
seizures and are controlled with titrated doses of IV diazepam:
give 5 mg every 2–5 minutes until gentle sedation is achieved and
the heart rate falls towards 100 beats/minute.
• Hyperthermia is a feature of severe serotonin syndrome and must
be immediately controlled. Temperature >38.5°C is an indication
for continuous core-temperature monitoring, benzodiazepine
sedation and fluid resuscitation. Temperature >39.5°C requires
rapid treatment to prevent multiple organ failure and neurological
injury. Paralysis, intubation and ventilation are indicated, as
described in Chapter 2.8: Serotonin syndrome.
• General supportive care measures as outlined in Chapter 1.4:
Supportive care and monitoring are indicated.
ERRNVPHGLFRVRUJ
Decontamination
• Activated charcoal is administered to patients who are alert and
cooperative and present within 2 hours following ingestion of
>4.5 g of venlafaxine or desvenlafaxine.
• Activated charcoal is contraindicated in the awake patient with
more delayed presentation or symptoms, due to the risk of
seizures.
Antidotes
• None available.
SPECIFIC TOXINS

• Because of the risk of seizures following venlafaxine or
desvenlafaxine overdose, all patients must be observed with IV
access in place for a minimum of 16 hours and until symptom
free. Seizures can be delayed up to 24 hours post ingestion in
some individuals.
• For ingestions <4.5 g, cardiac monitoring is not required after the
first 6 hours, provided the ECG demonstrates normal QRS and
QT intervals at that time.
398
• Patients who ingest >4.5 g require cardiac monitoring and serial
39
ECGs for a period of 12 hours post ingestion. ECG monitoring

8
may then cease if there is no evidence of QRS or QT prolongation.

• Patients with severe venlafaxine intoxication or serotonin
TOXICOLOGY HANDBOOK
syndrome require management in an intensive care unit.
HANDY TIPS
• Early administration of titrated doses of intravenous
benzodiazepines may prevent seizures. The dose is titrated to
achieve a calm patient and a fall in the heart rate towards 100
beats/minute.
• Coma is not secondary to venlafaxine intoxication and indicates
co-ingestion or complication.
PITFALLS
• Failure to anticipate and prepare for delayed onset of symptoms
and seizures.
• Failure to administer benzodiazepines early and in sufficient dose.
• Administration of activated charcoal or initiation of whole bowel
irrigation (WBI) shortly before onset of seizures or cardiovascular
toxicity.
CONTROVERSIES
• Both single-dose oral activated charcoal and WBI reduce
venlafaxine absorption, with the combination of both treatments
producing the greatest reduction in maximal venlafaxine
concentrations. However, the risk of seizures occurring following
delayed administration of activated charcoal or during WBI means
that a risk–benefit analysis does not clearly favour these
interventions.
ERRNVPHGLFRVRUJ
• There is little clinical experience with desvenlafaxine overdose and
it is not yet known whether the seizure risk is the same. A similar
management approach is advised until further clinical data
become available.
Presentations
Desvenlafaxine succinate controlled release tablets 50 mg (7, 28)
Desvenlafaxine succinate controlled release tablets 100 mg (28)
Venlafaxine controlled release tablets 37.5 mg (28)
Venlafaxine controlled release tablets 75 mg (28)
Venlafaxine controlled release tablets 150 mg (28)
References
Howell C, Wilson AD, Waring WS. Cardiovascular toxicity due to venlafaxine poisoning in
SPECIFIC TOXINS
adults: a review of 235 consecutive cases. British Journal of Clinical Pharmacology
2007; 64(2):192–197.
Isbister GK. Electrocardiogram changes and arrhythmias in venlafaxine overdose. British
Journal of Clinical Pharmacology 2009; 67(5):572–576.
Kumar VV, Oscarsson S, Friberg LE et al. The effect of decontamination procedures on
the pharmacokinetics of venlafaxine in overdose. Clinical Pharmacology and
Therapeutics 2009; 27:911–915.
Whyte IM, Dawson AH, Buckley NA. Relative toxicity of venlafaxine and selective
serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants.
Quarterly Journal of Medicine 2003; 96(5):369–374.
399
3.80 WARFARIN
TOXICOLOGY HANDBOOK
Over-anticoagulation is a frequent complication of warfarin therapy.
Deliberate self-poisoning with warfarin occurs in patients with or without
a requirement to maintain therapeutic anticoagulation. All patients are
usually asymptomatic at presentation. The approach to therapy is
determined by both the magnitude of over-anticoagulation and the
indication (or not) for therapeutic anticoagulation. Patients with active
bleeding require urgent combination reversal therapy. Vitamin K is the
specific antidote.
RISK ASSESSMENT
• Therapeutic over-anticoagulation presents as an asymptomatic
patient with an elevated INR or with active bleeding; the risk of
bleeding increases progressively as the INR rises above 5.
• In patients not on therapeutic warfarin who overdose:
— Acute ingestion <0.5 mg/kg is unlikely to cause a clinically
significant increase in INR
— Acute ingestion >2 mg/kg can produce a significant increase
in INR within 72 hours.
• Active bleeding constitutes an emergency and requires urgent
combination therapy (see below).
• Children: single acute unintentional ingestion of <0.5 mg/kg does
not present a risk of significant anticoagulation and does not
require investigation or treatment.
Toxic mechanism
Warfarin inhibits vitamin K metabolism, leading to depletion of the active reduced form.
Vitamin K is a cofactor required for the synthesis of coagulation factors II, VII, IX, and X
ERRNVPHGLFRVRUJ
(plus proteins C and S). The observed >12 hour delay before anticoagulation occurs is
secondary to the half-lives of existing vitamin K-dependent coagulation factors (6, 24, 40
and 60 hours for factors VII, IX, X and II, respectively). Peak effects are observed by 72
hours. Toxicity renders patients coagulopathic and vulnerable to haemorrhage.
Toxicokinetics
Warfarin is rapidly absorbed with 100% bioavailability. It has a small volume of
distribution (0.2 L/kg) and is 99% protein bound. Warfarin is metabolised in the liver
(cytochrome P450) to form metabolites that undergo enterohepatic recirculation.
Warfarin and its metabolites are excreted in urine and faeces with an elimination half-life
of 35 hours.
CLINICAL FEATURES
• Over-anticoagulated patients are usually asymptomatic.
• Severe coagulopathy may manifest as bruising, petechial or
SPECIFIC TOXINS
purpural rashes, gingival bleeding, epistaxis, gastrointestinal

bleeding or haematuria.
INVESTIGATIONS
• Management of warfarin-induced coagulopathy is based on
measurement of INR.
• Other investigations are performed to assess potential
complications as dictated by the individual risk assessment.
400 Screening tests in deliberate self-poisoning
40

0

TOXICOLOGY HANDBOOK
• INR
— In patients not previously anticoagulated, the INR is normal
for the first 12–24 hours after accidental or deliberate
overdose and a normal INR at 48 hours excludes warfarin
overdose.
— In patients with excessive anticoagulation, but a therapeutic
requirement, the INR is measured at presentation and at
6-hourly intervals thereafter.
MANAGEMENT
• If there is active uncontrolled haemorrhage, administer
prothrombin complex concentrate (25–50 IU/kg), fresh frozen
plasma (150–300 mL or 10–15 mL/kg) if prothrombin complex
concentrate is unavailable and vitamin K 5–10 mg IV.
Decontamination
• Following deliberate self-poisoning in cooperative patients on
therapeutic anticoagulation, administer 50 g oral activated
charcoal if they present within 1 hour of ingestion.
• Activated charcoal is not indicated in other patients.
ERRNVPHGLFRVRUJ
Antidotes
• Vitamin K (phytomenadione) is administered prophylactically to
patients who have ingested a potentially anticoagulating dose of
warfarin but have no therapeutic requirement for anticoagulation.
This obviates the need for repetitive coagulation testing. In
patients with a therapeutic requirement for anticoagulation,
vitamin K dose is carefully titrated in an effort to maintain an INR
in the optimal therapeutic range (see Chapter 4.29: Vitamin K).
• Accepted guidelines for management of therapeutic over-
anticoagulation, including vitamin K administration, are shown in
Appendix 5: Therapeutic over-warfarinisation.
SPECIFIC TOXINS
• Children who ingest <0.5 mg/kg do not required medical
assessment or observation.
• Children who ingest >0.5 mg/kg are given 10 mg vitamin K PO
and discharged. They do not require INRs or follow-up.
• Patients with no therapeutic requirement for anticoagulation are
treated with oral vitamin K (5 mg bd for 2 days) and medically
cleared. Follow-up INR is indicated at 48 hours 401
• Patients with a therapeutic requirement for anticoagulation are
admitted and receive titrated vitamin K doses, as discussed in
Chapter 4.29: Vitamin K.
TOXICOLOGY HANDBOOK
• Therapeutic over-anticoagulation is managed on an outpatient
basis, unless there is active bleeding or an INR >9.
HANDY TIP
• Warfarin levels may be useful in cases where paediatric non-
accidental injury or occult poisoning is suspected.
PITFALL
• Failure to carefully titrate vitamin K dose in patients requiring
therapeutic anticoagulation.
Presentations
Warfarin 1 mg tablets (50)
References
Isbister GK, Hackett LP, Whyte, IM. Intentional warfarin overdose. Therapeutic Drug
Monitoring 2003; 25(6):715–722.
Levine M, Pizon AE, Padilla-Jones A, Ruha A-M. Warfarin overdose: a 25-year
experience. Journal of Medical Toxicology 2014: doi 10.1007.
Tran HA, Chanilal SD, Harper PL et al. An update of consensus guidelines for warfarin
reversal. Medical Journal of Australia 2013: 198(4):1–7.
ERRNVPHGLFRVRUJ
CHAPTER 4
ANTIDOTES
4.1 Atropine 404

4.2 Calcium 405
4.3 Cyproheptadine 408
4.4 Desferrioxamine 409
4.5 Dicobalt edetate 411
4.6 Digoxin immune Fab 413
4.7 Dimercaprol 416
4.8 Ethanol 418
4.9 Flumazenil 420
4.10 Folinic acid 422
4.11 Fomepizole 424
4.12 Glucose 425
4.13 Hydroxocobalamin 427
4.14 Insulin (high-dose) 430
4.15 Intravenous lipid emulsion 432
4.16 Methylene blue 433
4.17 N-acetylcysteine 435
4.18 Naloxone 438
4.19 Octreotide 441
4.20 Penicillamine 442
4.21 Physostigmine 444
4.22 Pralidoxime 446
4.23 Pyridoxine 448
4.24 Sodium bicarbonate 450
4.25 Sodium calcium edetate 453
4.26 Sodium thiosulfate 455
4.27 Succimer 457
4.28 Vitamin K 459
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4.1 ATROPINE
Atropine is a competitive muscarinic antagonist, used to treat drug-
induced bradycardia and poisoning by acetylcholinesterase inhibitors.
Presentations
Atropine sulfate 0.1 mg/mL prefilled syringe (10 mL)
Atropine sulfate 0.4 mg/mL ampoules
TOXICOLOGICAL INDICATIONS
• Poisoning by agents that impair AV conduction such as cardiac
glycosides, beta-blockers and calcium channel blockers
• Organophosphate and carbamate poisoning
ANTIDOTES
CONTRAINDICATIONS
• Relative contraindications include:
— Closed angle glaucoma
— Obstructive disease of the gastrointestinal tract
— Obstructive uropathy.
Mechanism of action
404 Atropine is a competitive antagonist of acetylcholine at muscarinic receptors. It reverses
the excessive parasympathetic stimulation that results from inhibition of
40
acetylcholinesterase. It does not act at nicotinic receptors.

4
TOXICOLOGY HANDBOOK
Pharmacokinetics
Atropine has a poor oral bioavailability and undergoes hepatic metabolism with an
elimination half-life of 2–4 hours. It crosses the blood–brain and placental barriers. About
50% is excreted unchanged in urine.
ADMINISTRATION
• Place the patient in a monitored area where equipment,
drugs and personnel are available to provide full
resuscitative care.
Organophosphate and carbamate poisoning
• Administer an initial IV bolus of 1.2 mg.
• Further doses are given every 2–3 minutes, doubling the dose
each time until drying of respiratory secretions is achieved. Heart
rate is not a useful end point as tachycardia may persist due to
nicotinic effects or respiratory distress.
• Very large doses (up to 100 mg) may be required in severe cases
and ongoing atropine administration by infusion may be
necessary.
Bradycardia caused by drug-induced AV conduction blockade
• Administer an IV bolus of 0.6 mg.
• Repeat doses of 0.6 mg are given as required up to a maximum
of 1.8 mg.
ERRNVPHGLFRVRUJ
THERAPEUTIC END POINTS
• Drying of respiratory secretions in organophosphate poisoning.
• Note: The development of anticholinergic features indicates
excessive dosing.
ADVERSE DRUG REACTIONS AND THEIR MANAGEMENT

• Excessive atropine administration manifests with clinical features
of anticholinergic poisoning, including delirium, tachycardia,
mydriasis and urinary retention.
— No further atropine should be administered while features of
anticholinergic poisoning are present.
— Benzodiazepine sedation may be necessary to control
delirium and an indwelling urinary catheter should be inserted
because of the risk of urinary retention.
Pregnancy: no restriction on use.
ANTIDOTES
Paediatric: initial paediatric dose is 20 microgram/kg.
HANDY TIP
• Very large doses of atropine may be required to treat
organophosphate poisoning—anticipate this need and procure
sufficient stocks as soon as possible.
405
PITFALLS
• Failure to administer sufficient doses of atropine in
organophosphate or carbamate poisoning.
TOXICOLOGY HANDBOOK
• Administration of excessive atropine leading to iatrogenic
References
Bardin PG, Van Eeden SF. Organophosphate poisoning: grading the severity and
comparing treatment between atropine and glycopyrrolate. Critical Care Medicine
1990; 18(9):956–960.
Eddleston M, Buckley NA, Eyer P et al. Management of acute organophosphorus
pesticide poisoning. Lancet 2008; 371:597–607.
4.2 CALCIUM
Calcium is a cation that is essential for normal organ (including muscle
and nerve tissue) and cell function.
Presentations
Calcium gluconate 1 g/10 mL vials (0.22 mmol calcium ions/mL)
Calcium gluconate 5 g/50 mL vials (0.22 mmol calcium ions/mL)
Calcium chloride 0.74 g/5 mL ampoules (1.01 mmol calcium ions/mL)
Calcium chloride 1 g/10 mL ampoules (0.68 mmol calcium ions/mL)
Calcium chloride 1 g/10 mL single-use syringe (0.68 mmol calcium ions/mL)
ERRNVPHGLFRVRUJ
• Calcium channel blocker poisoning
• Hydrofluoric acid skin exposure
• Hypocalcaemia of systemic fluorosis secondary to ingestion of, or
extensive skin exposure to, hydrofluoric acid
• Hypocalcaemia secondary to ethylene glycol poisoning
• Iatrogenic hypermagnesaemia
• Hyperkalaemia
CONTRAINDICATIONS
• Hypercalcaemia
• Digoxin toxicity (controversial)
Mechanism of action
Calcium acts as a physiological antagonist to the effects of hyperkalaemia and
hypermagnesaemia on the cardiac conducting system and skeletal muscle.
Administration of calcium in hypocalcaemic states restores or maintains ionised calcium
at a concentration sufficient to prevent cardiac dysrhythmias. In hydrofluoric acid
ANTIDOTES
poisoning, calcium ions bind to fluoride ions and prevent further tissue penetration and
injury. Elevation of the ionised calcium concentration may help overcome the deleterious
effects of calcium channel blocker poisoning.
Pharmacokinetics
Ninety-nine per cent of the body’s calcium is contained within bone. Of the calcium in
plasma, about half is ionised and physiologically active while the other half is bound to
albumin. Plasma calcium concentration is maintained at close to 2.5 mmol/L by a
406 number of hormonal homeostatic mechanisms.
40
6
ADMINISTRATION
• Place the patient in a monitored area where equipment, drugs
TOXICOLOGY HANDBOOK
and personnel are available to provide full resuscitative care.

• Cardiac monitoring is mandatory during infusion of calcium salts.
Hypocalcaemia/hyperkalaemia/hypermagnesaemia
• Administer 0.5–1 g (5–10 mL) of calcium chloride or 1–2 g
(10–20 mL) of calcium gluconate IV over 5–10 minutes, preferably
into a large vein. Repeat every 10–15 minutes as required.
• Further administration of calcium salts is guided by serum calcium
concentrations, which should not exceed the normal range.
Calcium channel blocker poisoning
• Give 2 g (20 mL) of calcium chloride IV or 6 g (60 mL) of calcium
gluconate IV over 5–10 minutes. This dose may be repeated every
20 minutes for up to three doses.
Hydrofluoric acid skin exposure
• Topical 2.5% calcium gel
— Minor burns.
— For burns to the hand, put gel in a glove and place hand in
the glove.
• Local injection of calcium gluconate 1 g/10 mL
— Consider if topical application fails to stop pain.
— Inject 0.5 mL/cm2 depots intradermally and subcutaneously
using a 25 G needle to achieve local tissue infiltration.
— Not suitable for finger exposures.
— Do not inject calcium chloride, as this can cause tissue injury.
ERRNVPHGLFRVRUJ
• Bier’s block (forearm regional intravenous injection)
— Consider for large HF exposures to fingers, hand or forearm
or if gel application to these regions has failed.
— Insert intravenous line distally in affected forearm.
— Dilute 1 g (10 mL) calcium gluconate in 40 mL of normal
saline.
— Inject diluted calcium gluconate solution intravenously with
pneumatic tourniquet inflated (Bier’s block technique).
— Release cuff after 20 minutes.
• Intra-arterial infusion
— Insert arterial line into radial, brachial or femoral artery of
affected limb.
— Dilute 1 g (10 mL) of calcium gluconate in 40 mL of normal
saline.
— Infuse diluted calcium gluconate solution over 4 hours and
repeat as necessary.
Hydrofluoric acid inhalation injury
• Give nebulised 2.5% calcium gluconate solution.
ANTIDOTES
• Hypocalcaemia/hypermagnesaemia/hyperkalaemia: normalisation
of serum calcium
• Calcium channel blocker poisoning: haemodynamic improvement
• Hydrofluoric acid skin exposure: resolution of pain
407
• Transient hypercalcaemia manifested by tetany and seizures
— Interrupt calcium salt administration and check serum calcium
TOXICOLOGY HANDBOOK
concentration.
• Vasodilation, hypotension, dysrhythmias, syncope or cardiac
arrest due to over-rapid administration
— Interrupt calcium salt administration.
— Institute advanced cardiac life support as appropriate.
• Local tissue damage from extravasation of calcium chloride
Paediatric: paediatric dose for hypocalcaemia or calcium channel
blocker poisoning is 1.0 mL/kg 10% calcium gluconate solution over
5–10 minutes and repeated after 10–15 minutes if necessary.
HANDY TIPS
• QT duration and clinical features of hypocalcaemia may be a
more useful guide to calcium requirements than serum calcium
concentrations.
• Calcium gluconate can safely be given via a peripheral line
whereas calcium chloride is best given via a central line because
of the risk of tissue damage from extravasation. It should not be
given in the same intravenous line as sodium bicarbonate.
• 2.5% calcium gluconate gel for treatment of skin exposure to
hydrofluoric acid can be prepared by mixing 10 mL of 10%
ERRNVPHGLFRVRUJ
calcium gluconate solution with 30 mL lubricant gel (e.g. K-Y jelly)
or by mixing 3.5 g calcium gluconate powder in 150 mL of
lubricant gel.
• Do not use calcium salt solution to irrigate the eye after ocular
hydrofluoric acid exposure as it may cause corrosive injury.
• Pain refractory to calcium administration in late-presentation
hydrofluoric acid burns may indicate established tissue damage
rather than therapeutic failure.
• Very large doses of calcium chloride may be required to maintain
eucalcaemia following hydrofluoric acid ingestion.
CONTROVERSIES
• Efficacy and optimal dosing of calcium salts in calcium channel
blocker poisoning.
• Most effective route of administration of calcium salts for
hydrofluoric acid skin exposures.
References
ANTIDOTES
Graudins A, Burns MJ, Aaron CK. Regional intravenous infusion of calcium gluconate for
hydrofluoric acid burns of the upper extremity. Annals of Emergency Medicine 1997;
30:604–607.
Vance MV, Curry SC, Kunkel DB et al. Digital hydrofluoric acid burns: treatment with
intraarterial calcium infusion. Annals of Emergency Medicine 1986; 15:890–896.
408 4.3 CYPROHEPTADINE

40
8
Cyproheptadine is a histamine and serotonin antagonist with

TOXICOLOGY HANDBOOK
anticholinergic properties. It has been advocated for control of

symptoms in mild-to-moderate serotonin syndrome.
Presentations
Cyproheptadine 4 mg tablets (50, 100)
TOXICOLOGICAL INDICATION
• Mild-to-moderate serotonin syndrome
CONTRAINDICATIONS
• Known hypersensitivity
• Acute asthma
• Closed angle glaucoma
• Bladder neck obstruction
Mechanism of action
Cyproheptadine acts as a competitive antagonist at histamine H1 and serotonin
5-HT1A and 5-HT2 receptors. It exerts centrally mediated hormonal effects such as the
inhibition of adrenocorticotrophic hormone (ACTH), probably secondary to serotonin
antagonism. It also has moderate local anaesthetic action and mild peripheral
anticholinergic action.
Pharmacokinetics
Cyproheptadine is well absorbed following oral administration, with peak plasma levels
observed after 1–3 hours. Elimination is primarily by hepatic glucuronidation with urinary
excretion of metabolites.
ERRNVPHGLFRVRUJ
ADMINISTRATION
• Administer an initial dose of 8 mg orally and observe for clinical
response.
• If a response is observed, continue treatment with 8 mg every 8
hours for 24 hours.
• Therapy should not be required beyond 24 hours, provided
agents that may precipitate serotonin syndrome are withheld.
• A longer duration of therapy may be required to treat serotonin
syndrome associated with an irreversible MAO inhibitor.

• Resolution or amelioration of the clinical features associated with
serotonin syndrome within 1–2 hours of the initial dose

• Insignificant adverse effects at therapeutic doses
ANTIDOTES
Paediatric: paediatric dose is not well established. For 7–14-year-
olds an initial dose of 4 mg followed by 4 mg every 8 hours for 24
hours is suggested.
HANDY TIPS 409

• Cyproheptadine is not a life-saving antidote. It may ameliorate the
symptoms of mild-to-moderate serotonin syndrome, but a good
outcome will be achieved in these cases with simple supportive
TOXICOLOGY HANDBOOK
care including mild benzodiazepine sedation.
• Cyproheptadine is not useful in the management of severe
serotonin syndrome. Early intubation and neuromuscular paralysis
is the key to achieving a good outcome in this circumstance.
PITFALLS
• Failure to assess clinical response to initial dose.
• Reliance on cyproheptadine to the detriment of good supportive
care in the management of serotonin syndrome.
Reference
Graudins A, Stearman A, Chan B. Treatment of the serotonin syndrome with
cyproheptadine. Journal of Emergency Medicine 1998; 16(4):615–619.
4.4 DESFERRIOXAMINE
An effective iron chelator that is used to treat systemic iron toxicity or
prevent the development of systemic toxicity following acute iron
overdose.
Presentations
Desferrioxamine mesylate 500 mg vials (powder for reconstitution)
Desferrioxamine mesylate 2 g vials (powder for reconstitution)
ERRNVPHGLFRVRUJ
• Acute iron poisoning
— Established systemic iron toxicity with clinical features of
severe gastroenteritis, shock, metabolic acidosis and altered
mental state
— Significant risk of systemic iron toxicity, as predicted by
serum iron levels >90 micromol/L or 500 microgram/dL at 4–6
hours post ingestion
• Chronic iron overload
CONTRAINDICATIONS
• None
Mechanism of action
Desferrioxamine (DFO) binds avidly to free ferric ion in the plasma to form ferrioxamine.
This stable complex is highly water soluble and is readily excreted in the urine. DFO is
able to remove iron bound to transferrin and haemosiderin, but not from outside the
intravascular compartment. 1000 mg of DFO is able to bind 85 mg of ferric iron.
ANTIDOTES
Pharmacokinetics
The volume of distribution is 1 L/kg and it does not substantially enter tissue
compartments. Steady-state concentrations are achieved at 6–12 hours during
intravenous infusion. DFO undergoes hepatic metabolism, producing multiple
metabolites, one of which is responsible for the drug’s toxic effects. Some drug is
excreted unchanged in the urine. The elimination half-life is 3 hours but substantially
increased in renal failure. Ferrioxamine has a smaller volume of distribution than DFO, is
410 not metabolised but excreted unchanged in the urine, and is dialysable.
41
0
ADMINISTRATION
•
TOXICOLOGY HANDBOOK
Cardiac monitoring is mandatory during DFO administration.

• Reconstitute 500 mg of powder with 5 mL sterile water and dilute
in 100 mL normal saline or 5% dextrose.
• Commence IV infusion at an initial dose of 15 mg/kg/hour.
• Reduce the infusion rate if hypotension develops.
• The rate may be increased in life-threatening toxicity up to 40 mg/
kg/hour, providing significant hypotension does not supervene.
• Continue the infusion until therapeutic end points have been
achieved, but avoid infusions prolonged >24 hours.

• Patient clinically stable
• Serum iron <60 micromol/L (350 microgram/dL)

• Hypersensitivity reactions
• Hypotension, especially with rapid or high-dose IV infusion
— Reduce infusion rate if hypotension occurs.
• With prolonged infusions (>24 hours), possible development of
ARDS
• Toxic retinopathy
• Secondary infections including Yersinia sepsis and mucormycosis:
ferrioxamine complex acts as a siderophore promoting growth of
these organisms
ERRNVPHGLFRVRUJ
Pregnancy: there is no evidence of human teratogenicity with DFO,
and although it is not known if DFO crosses the placenta, it should
never be withheld in the treatment of pregnant patients with severe
iron poisoning.
Paediatric: administration and dose are as for adults.
HANDY TIPS
• DFO is ideally administered before iron moves intracellularly and
systemic toxicity develops.
• Intramuscular DFO administration is not indicated in acute iron
poisoning.
• Although urine may change to the classical vin rosé colour during
DFO administration, this is an unreliable sign of effective chelation.
• Six hours of DFO chelation is usually sufficient and it is extremely
rare to require therapy beyond 24 hours.
ANTIDOTES
PITFALLS
• Administration of DFO when not clinically indicated
• Excessive duration of DFO administration
CONTROVERSIES
• There are no controlled trials or dose–response studies to support
the efficacy of DFO chelation for human iron poisoning.
411
• The optimal indications, dose, route of administration and end
points for therapy are not well defined.
TOXICOLOGY HANDBOOK
References
Howland MA. Risks of parenteral deferoxamine for acute iron poisoning. Journal of
Tenenbein M. Benefits of parenteral deferoxamine for acute iron poisoning. Journal of
4.5 DICOBALT EDETATE

Cobalt edetate, Cobalt EDTA, Cobalt tetracemate
This agent was developed as a cyanide antidote based on the known
ability of cobalt to form stable complexes with cyanide. The severe direct
toxic effects that occur when it is administered to a patient without
cyanide poisoning limit the use of this agent.
Presentations
Dicobalt edetate 300 mg/20 mL ampoules
• Unequivocal acute cyanide poisoning
CONTRAINDICATIONS
• Suspected cyanide poisoning without definite signs of poisoning,
such as impairment or loss of consciousness
ERRNVPHGLFRVRUJ
Pharmacodynamics
Dicobalt edetate is an inorganic cobalt salt. At least one of the cobalt atoms is available
to bind cyanide. One mole of cobalt binds six moles of cyanide to form stable
complexes. Cobalt cyanides are much less toxic than free cyanide.
Pharmacokinetics
Dicobalt edetate is able to cross the blood–brain barrier. The cyanide–cobalt complex is
excreted in the urine.
ADMINISTRATION
• This antidote is only administered to critically ill patients in a
monitored area where equipment, drugs and personnel are
available to provide full resuscitative care. Cardiac monitoring is
mandatory.
• Administer 300 mg (1 ampoule) IV over 1 minute, followed
immediately with 50 mL of 50% dextrose IV to protect against
toxicity.
• A repeat second or third dose of 300 mg is given if an immediate
ANTIDOTES
clinical response is not observed.

• Improvement in conscious state
• Haemodynamic stability
• Improvement in metabolic acidosis
412
ADVERSE DRUG REACTIONS
41
• Significant adverse reactions have been reported, usually when it

2
is inappropriately administered in the absence of cyanide

TOXICOLOGY HANDBOOK
poisoning.
• These reactions are due to direct toxicity of the cobalt salt and
include: seizures; oedema of the face, larynx and neck; chest
pain; dyspnoea; hypotension; vomiting; and urticarial rashes.
Pregnancy: safety in pregnancy is not confirmed. Administration
should not be withheld if indicated.
Paediatric: paediatric dose is 7.5 mg/kg IV (maximum dose 300 mg).
HANDY TIPS
• Never give dicobalt edetate to a patient without clinical features
of definite severe cyanide poisoning including impaired level of
consciousness.
• The occurrence of adverse outcomes is minimised by adhering to
strict clinical criteria for giving the antidote.
PITFALLS
• Administration of dicobalt edetate to a patient without cyanide
poisoning or one displaying only minor clinical manifestations of
cyanide poisoning
• Inadvertent or mistaken administration of sodium calcium edetate
(EDTA), an antidote used in the treatment of lead poisoning
ERRNVPHGLFRVRUJ
CONTROVERSY
• The relative efficacy of dicobalt edetate as an antidote for cyanide
poisoning in humans has not been established.
References
Hall A, Saiers J, Baud F. Which cyanide antidote? Critical Reviews in Toxicology 2009;
39(7):541–552.
4.6 DIGOXIN IMMUNE FAB

These antibody fragments promptly and safely reverse the toxicity of
digoxin and other cardiac glycosides.
Presentations
Digoxin-specific immune antigen binding fragments as lyophilised powder 40 mg ampoules
ANTIDOTES
Cardiac glycoside poisoning where there is an imminent threat to life
or where the risk assessment suggests such a threat is an absolute
indication for immediate administration of digoxin immune Fab.
Administration is also indicated in any patient whose manifestations
of digoxin toxicity are sufficient to warrant inpatient care. More 413
specifically:
• Acute digoxin overdose
— Cardiac arrest
TOXICOLOGY HANDBOOK
— Ingested dose >10 mg (adult) or >4 mg (child)
— Serum digoxin level >15 nmol/L (12 ng/mL)
— Serum potassium >5 mmol/L
• Chronic digoxin poisoning
— Cardiac arrest
— Cardiac dysrhythmia or increased automaticity not likely to be
tolerated for a prolonged period
— Moderate-to-severe gastrointestinal symptoms
— Any symptoms in presence of impaired renal function
• Other cardiac glycoside poisoning
— Oleander
— Bufotoxin (cane toad)
CONTRAINDICATIONS
• None
Mechanism of action
Digoxin immune Fab is created by papain cleavage of IgG molecules raised in sheep
against digoxin bound to albumin. 40 mg (one ampoule) of Fab binds 0.5 mg of digoxin.
Digoxin immune Fab binds directly to the free intravascular and interstitial digoxin with
much greater affinity than the Na+/K+-ATPase receptor. A concentration gradient is
created and intracellular digoxin dissociates from tissues and moves to the intravascular
space where binding to immune Fab continues.
ERRNVPHGLFRVRUJ
Pharmacokinetics
Digoxin bound to Fab fragments is excreted in the urine, with an elimination half-life of
16–30 hours.
ADMINISTRATION
Cardiac monitoring is mandatory during antidote administration
and until toxicity is reversed.
• Calculate the dose required (see below), dilute in 100 mL normal
saline and administer over 30 minutes.
• Dose is calculated on the presumption that one ampoule of Fab
binds 0.5 mg of digoxin.
CALCULATION OF DOSE
• Acute digoxin overdose
— Known digoxin dose
– Number of ampoules = ingested dose (mg) × 0.8
ANTIDOTES
(bioavailability) × 2
— Unknown digoxin dose
– Commence empiric dosing with 5 ampoules if the patient
is haemodynamically stable or 10 ampoules if unstable.
– Give repeat doses of 5 ampoules every 30 minutes until
reversal of digoxin toxicity is achieved.
414 • Chronic digoxin poisoning
— Number of ampoules
41
serum digoxin (ng/mL ) × body weight (kg)

4
=
100
TOXICOLOGY HANDBOOK
— Alternatively, commence empiric dosing with 2 ampoules

and observe for clinical response. If there is no reversal
of digoxin toxicity after 30 minutes, give a further 2
ampoules.
• Other cardiac glycoside poisoning
— If the patient is stable, commence with an empiric dose of 5
ampoules and repeat every 30 minutes until reversal of
toxicity is observed.
— Large doses may be required before a clinical response is
achieved. Up to 30 ampoules have been used to successfully
reverse severe yellow oleander poisoning.
DURATION OF TREATMENT
• A single dose given over 30 minutes is usually sufficient.
• Following an adequate dose, a response is normally apparent by
20 minutes and maximal by 4 hours.
• Rarely, digoxin toxicity may recur beyond 24 hours and
necessitate further administration of digoxin immune Fab.

• Restoration of normal cardiac rhythm and conduction
• Resolution of gastrointestinal symptoms
ERRNVPHGLFRVRUJ
This is an extremely safe antidote – adverse effects of any kind occur in less
than 5% of cases. Adverse effects include:
• Hypokalaemia
• Allergy (extremely rare)
• Exacerbation of underlying cardiac failure
• Loss of rate control of preexisting atrial fibrillation.
Paediatric: no restriction on use.
HANDY TIPS
• In cardiac arrest thought to be due to digoxin poisoning, give
high-dose digoxin immune Fab (20 ampoules if available) by rapid
intravenous injection, while continuing cardiopulmonary
resuscitation.
•
ANTIDOTES
Digoxin levels following treatment may appear very high. This is
because most serum digoxin assays measure both free and
Fab-bound digoxin. Some laboratories are able to assay free
digoxin.
• Hyperkalaemia due to acute digoxin poisoning is treated with Fab,
not intravenous calcium, as digoxin causes elevation in
intracellular myocardial calcium levels.
• It is not necessary to bind the total body digoxin load to control 415
toxicity. The administration of less than the calculated dose of
digoxin immune Fab may still be sufficient.
•
TOXICOLOGY HANDBOOK
Administration of digoxin immune Fab to patients with non-life
threatening chronic digoxin toxicity is shown to significantly
reduce length-of-stay in hospital.
PITFALLS
• Unavailability of sufficient digoxin immune Fab to treat life-
threatening poisoning.
• Withholding digoxin immune Fab from patients with chronic
digoxin poisoning because of concerns about expense of the
antidote. The risk of death and cost of prolonged unnecessary
admission to a monitored bed greatly exceed the cost of 2
ampoules of digoxin immune Fab.
CONTROVERSIES
• It may be pharmacokinetically more appropriate to give smaller
initial doses of digoxin immune Fab and follow up with repeat
doses or an infusion.
• The dose of digoxin immune Fab is not well defined in
poisoning by other cardiac glycosides, such as those contained in
oleander.
References
ERRNVPHGLFRVRUJ
Bateman DN. Digoxin-specific antibody fragments: how much and when? Toxicological
Reviews 2004; 23(3):135–143.
Di Domenico R, Walton S, Sanoski CA et al. Analysis of the use of digoxin Fab for the
treatment of non life threatening digoxin toxicity. Journal of Cardiovascular
Pharmacology and Therapeutics 2000; 5(2):77–85.
Eddleston M, Rajapakse S, Rajakanthan JS et al. Anti-digoxin Fab fragments in
cardiotoxicity induced by ingestion of yellow oleander: a randomised controlled trial.
Lancet 2000; 355(9208):967–972.
Lapostolle F, Borron SW, Verdier C et al. Digoxin-specific Fab fragments as single
first-line therapy in digitalis poisoning. Critical Care Medicine 2008; 36:3014–3018.
Woolf AD, Wenger T, Smith TW et al. The use of digoxin-specific Fab fragments for
severe digitalis intoxication in children. New England Journal of Medicine 1992;
326:1739–1744.
4.7 DIMERCAPROL
British antilewisite, 2,3-dimercaptopropanol
This rarely used intramuscular chelator is the most toxic of all chelating
ANTIDOTES
agents and is reserved for the treatment of severe poisoning from lead,
inorganic arsenic and mercury.
Presentations
Dimercaprol 300 mg, benzyl benzoate 600 mg, peanut oil 2100 mg/3 mL ampoules
416 TOXICOLOGICAL INDICATIONS

• Arsenic poisoning
41
• Inorganic mercury poisoning

6
• Gold intoxication
TOXICOLOGY HANDBOOK
• Severe lead poisoning or lead encephalopathy (adjunct to EDTA)

• Other heavy metal poisoning
— Dimercaprol has been used to chelate bismuth, antimony,
chromium, nickel, tungsten and zinc, but clinical experience is
limited.
CONTRAINDICATIONS
• Peanut allergy
• G6PD deficiency
Pharmacodynamics
Dimercaprol binds metal ions to form stable dimercaptides, which can then be excreted
in the urine.
Pharmacokinetics
Dimercaprol is not absorbed orally. In fact, because it is formulated in peanut oil, it is
only suitable for IM administration. Blood concentrations peak about 30 minutes after IM
administration and distribution occurs rapidly. It is metabolised predominantly by
glucuronic conjugation and the metabolites are excreted in the urine. Dimercaprol–metal
conjugates are removed by dialysis.
ADMINISTRATION
• Therapy is always commenced in an intensive care setting
due to the severity of the underlying condition and adverse
effects.
ERRNVPHGLFRVRUJ
• Alkalinise the urine prior to commencing therapy in order to
reduce risk of nephrotoxicity (prevents dissociation of
dimercaprol–metal conjugates in the urine).
Severe inorganic arsenic or mercury poisoning
• Give 3 mg/kg IM every 4 hours for 48 hours
then
• Give 3 mg/kg IM every 12 hours for 7–10 days depending on
clinical response.
Lead encephalopathy
• Commence dimercaprol 4 hours before commencing EDTA.
• Give 4 mg/kg every 4 hours for 5 days.
• See Chapter 4.25: Sodium calcium edetate for further
information.

Dimercaprol is associated with an extremely high incidence (about
50%) of adverse effects at therapeutic dose. These include:
• Pain and sterile abscess formation at injection sites
ANTIDOTES
• Fever (especially in children) and myalgia
• Chest pain, hypertension and tachycardia
• Headache, nausea and vomiting
• Peripheral paraesthesias; burning sensation of lips, mouth, throat
and eyes
• Lacrimation, rhinorrhoea and excessive salivation
• Risk of intravascular haemolysis in patients with G6PD deficiency 417
• Nephrotoxicity secondary to the dissociation of dimercaprol–metal
complexes in acid urine
• Hypertensive encephalopathy at supratherapeutic doses.
TOXICOLOGY HANDBOOK
Unfortunately, many of these adverse effects may need to be
tolerated in view of the severity of the underlying intoxication and lack
of alternative viable chelating agents.
For life-threatening adverse effects, subsequent doses should be
reduced.
Pregnancy: safety not established. Administration should not be
withheld if clinically indicated.
Lactation: safety not established.
Paediatric: dose and administration as for adults.
HANDY TIPS
• Never give intravenously.
• Dimercaprol is most effective when administered shortly after the
exposure.
• Never give more than 4 mg/kg as a single dose due to high
incidence of adverse effects.
• If the patient is well enough, chelation with the orally-active
analogue of dimercaprol (succimer) is always preferable.
PITFALL
• Failure to access supplies promptly – dimercaprol is difficult to
obtain and stocked by relatively few hospitals.
ERRNVPHGLFRVRUJ
CONTROVERSY
• Dosing regimens are usually historical and clinical efficacy is
poorly established.
References
Gold H. BAL (British anti-lewisite). American Journal of Medicine 1948; 4:1.
Vilensky JA, Redman K. British anti-lewisite (dimercaprol): an amazing history. Annals of
4.8 ETHANOL
Competitively blocks the formation of toxic metabolites in toxic alcohol
ingestions by having a higher affinity for the enzyme alcohol
dehydrogenase (ADH). Its chief application is in methanol and ethylene
glycol ingestions, although it has been used with other toxic alcohols.
Ethanol is now regarded as the second choice antidote in those
countries with access to the specific ADH blocker, fomepizole.
ANTIDOTES
Presentations
Pure ethanol 20 mL ampoule (pharmaceutical grade)
Commercial alcoholic beverages with alcohol content from 5% to 70%
418 • Methanol poisoning (confirmed or suspected)
• Ethylene glycol poisoning (confirmed or suspected)
41
8
CONTRAINDICATIONS
TOXICOLOGY HANDBOOK
• Recent ingestion of disulfiram (or drugs that may cause a

disulfiram-like reaction)
Mechanism of action
Alcohol dehydrogenase has a much higher affinity (up to 20×) for ethanol than for
ethylene glycol or methanol. Ethanol competitively inhibits the conversion of these
other alcohols to their toxic metabolites by blocking the receptor sites of ADH.
Inhibition is virtually complete at ethanol concentrations greater than 100 mg/dL
(22 mmol/L).
Pharmacokinetics
Ethanol is rapidly absorbed after oral administration and distributed throughout the total
body water. It rapidly crosses both the placenta and the blood–brain barrier. Elimination
is principally by enzymatic oxidation in the liver in a two-step process involving alcohol
dehydrogenase and aldehyde dehydrogenase. Metabolic capacity is saturated at
relatively low concentrations. The rate of metabolism is extremely variable between
individuals.
ADMINISTRATION
• Therapy should be commenced in a monitored area with
personnel and equipment available to monitor mental status and
blood or breath alcohol levels every 2 hours.
• Ethanol may be administered by the oral, nasogastric or
intravenous route to maintain a blood ethanol concentration of
100–150 mg/dL (22–33 mmol/L).
ERRNVPHGLFRVRUJ
Oral or nasogastric administration
• Loading dose: 1.8 mL/kg of 43% ethanol, or 3 × 40 mL shots of
vodka in a 70-kg adult.
• Note: Omit the loading dose of ethanol in the already ethanol-
intoxicated patient.
• Maintenance: 0.2–0.4 mL/kg/hour of 43% ethanol, or 40-mL shot
each hour.
Intravenous administration
• Loading dose: 8 mL/kg of 10% ethanol.
• Maintenance infusion rate: 1–2 mL/kg/hour of 10% ethanol.
• Note: A 10% ethanol solution is prepared by adding 100 mL of
100% ethanol to 900 mL of 5% dextrose.
• Remember: the required maintenance dose is extremely variable.
The doses outlined above are a guide only and must be adjusted
to maintain blood alcohol concentrations in the desired range.
• Continue maintenance ethanol therapy until the toxic alcohol
poisoning has been definitively treated with haemodialysis.
ANTIDOTES
• Local phlebitis from intravenous solutions
• Ethanol intoxication
— Reduce rate of ethanol administration if blood ethanol
concentration exceeds 150 mg/dL (33 mmol/L).
• Hypoglycaemia in children
419
Pregnancy: ethanol and the toxic alcohols readily cross the placenta.
There is no contraindication to ethanol administration in the pregnant
TOXICOLOGY HANDBOOK
woman with toxic alcohol poisoning.
Paediatric: there is no contraindication to ethanol administration in
the child with toxic alcohol poisoning, but the child should be
carefully monitored for hypoglycaemia.
HANDY TIPS
• Ethanol for intravenous therapy is difficult to procure – alcoholic
spirits suitable for oral administration are ubiquitous.
• Administration of ethanol may be delayed in the patient who
already has a high ethanol level.
• Breath ethanol estimations may be substituted for repeated blood
ethanol levels during maintenance therapy.
PITFALLS
• Delay in starting therapy.
• Failure to monitor blood ethanol levels closely resulting in sub- or
supratherapeutic concentrations.
CONTROVERSIES
• Relative merits of fomepizole over ethanol in the management of
toxic alcohol poisoning.
• Clinical efficacy of ethanol in the treatment of poisoning with
other toxic alcohols, including glycol ethers, diethylene glycol,
triethylene glycol, propylene glycol and butanediol.
• Necessity to continue to maintain ethanol levels after
commencement of haemodialysis.
ERRNVPHGLFRVRUJ
References
Barceloux DG, Krenzelok EK, Olson K et al. American Academy of Clinical Toxicology
Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Journal of
Beatty L, Green K, Magee K, Zed P. A systematic review of ethanol and fomepizole use
in toxic alcohol ingestion. Emergency Medicine International 2013; 2013:638057.
Lepik KJ, Levy AR, Sobolev BG et al. Adverse drug events associated with the antidotes
for methanol and ethylene glycol poisoning: a comparison of ethanol and
fomepizole. Annals of Emergency Medicine 2009; 53:439–450.
4.9 FLUMAZENIL
Competitive benzodiazepine antagonist with a limited role in the
management of benzodiazepine poisoning.
Presentations
Flumazenil 0.5 mg/5 mL ampoules
ANTIDOTES
• Benzodiazepine overdose
— Accidental paediatric ingestion with compromised airway and
breathing
— Deliberate self-poisoning with compromised airway and
breathing, and equipment and skills to intubate and ventilate
420 not readily available (rare)
42
— Note: Isolated benzodiazepine overdose rarely causes CNS

0
depression sufficient to warrant intervention.

• To confirm diagnosis of benzodiazepine intoxication
TOXICOLOGY HANDBOOK
— Useful if it avoids invasive or expensive further investigation to

exclude alternative diagnoses
• Reversal of procedural sedation with benzodiazepines
CONTRAINDICATIONS
• Known seizure disorder
• Known or suspected co-ingestion of pro-convulsant drugs
• Known or suspected benzodiazepine dependence
• QRS prolongation on ECG (suggests possibility of co-ingestion of
tricyclic antidepressant)
Mechanism of action
Flumazenil is a 1,4-imidazobenzodiazepine structurally similar to midazolam. It acts as a
competitive antagonist at the benzodiazepine receptor sites in the CNS. Binding inhibits
benzodiazepine activity at the GABA–benzodiazepine complex and reverses the CNS
effects of benzodiazepines.
Pharmacokinetics
Flumazenil has a volume of distribution of 1 L/kg at steady state. It undergoes rapid and
extensive hepatic metabolism to inactive metabolites. Elimination half-life is 40–80 minutes.
These pharmacokinetic properties are unaltered following benzodiazepine overdose.
ADMINISTRATION
• Flumazenil should only be administered in an environment where
equipment and personnel are available to manage a seizure.
ERRNVPHGLFRVRUJ
• Give an initial dose of 0.1–0.2 mg IV and repeat every minute until
reversal of sedation is achieved.
• Maximal response should be observed with a dose not exceeding
2 mg.
• Re-sedation is expected and normally occurs at around 90
minutes. If necessary, repeated doses may be given to maintain
adequate reversal of benzodiazepine sedation. Occasionally a
flumazenil infusion may be of value.
• Note: Patients must be observed for re-sedation for several hours
following the last dose of flumazenil.

Benzodiazepine withdrawal syndrome
• Manifests as agitation, tachycardia and seizures.
• Mild benzodiazepine withdrawal will be short-lived and does not
require specific management.
• Severe withdrawal syndrome requires administration of
benzodiazepines in titrated doses.
ANTIDOTES
Seizures
• Most commonly occur in patients with benzodiazepine
dependence, co-ingestion of pro-convulsant drugs or an
underlying seizure disorder.
• Withhold further flumazenil.
• Repeated or prolonged seizures require administration of
benzodiazepines in titrated doses.
421
TOXICOLOGY HANDBOOK
Paediatric: give 0.01–0.02 mg/kg repeated every minute as
necessary. Flumazenil administration is extremely safe in children who
have ingested benzodiazepines, as they are unlikely to be
benzodiazepine-dependent.
HANDY TIP
• Flumazenil may be life-saving if personnel and equipment for
definitive airway control are not available.
PITFALLS
• Unnecessary administration to patients with mild benzodiazepine
poisoning.
• Administration when contraindicated due to risk of seizures.
• Failure to observe for re-sedation.
CONTROVERSY
• Role of flumazenil in management of the undifferentiated overdose
patient.
References
Kreshak AA, Cantrell FL, Clark RF, Tomaszewski CA. A poison center’s ten-year
experience with flumazenil administration to acutely poisoned adults. The Journal of
ERRNVPHGLFRVRUJ
Ngo AS, Anthony CR, Samuel M et al. Should a benzodiazepine antagonist be used in
unconscious patients presenting to the emergency department? Resuscitation 2007;
74(1):27–37.
Seger D. Flumazenil: treatment or toxin. Journal of Toxicology – Clinical Toxicology 2004;
42(2):209–216.
The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group. Treatment of
benzodiazepine overdose with flumazenil. Clinical Therapeutics 1992; 14:978–995.
4.10 FOLINIC ACID

Leucovorin, 5-formyltetrahydrofolic acid
This agent is the active form of folic acid. It is routinely used for ‘folinic
acid rescue therapy’ following administration of high doses of parenteral
methotrexate in oncological practice. Its applications in clinical
toxicology are rather more limited.
Presentations
ANTIDOTES
Calcium folinate 15 mg tablets (10)

Calcium folinate 15 mg/2 mL ampoules
Calcium folinate 50 mg/5 mL plastic vials
Calcium folinate 100 mg/10 mL plastic vials
Calcium folinate 300 mg/30 mL plastic vial
422
42
• Supratherapeutic methotrexate ingestion

2
— This usually occurs in the context of accidental daily dosing of

TOXICOLOGY HANDBOOK
methotrexate rather than the usual weekly dosing.

— Folinic acid therapy is indicated if:
– Clinical features of methotrexate toxicity are evident
or
– The weekly dose has been administered daily for more
than 3 consecutive days.
• Single acute oral methotrexate overdose
— Methotrexate toxicity has never been reported in this
scenario.
— Folinic acid should be given empirically, if more than 500 mg
(5 mg/kg in children) is ingested, until methotrexate levels are
available to more fully assess risk of toxicity.
— If less than 500 mg of methotrexate is ingested, consider
folinic acid when methotrexate levels are not available within
24 hours.
• Adjunct treatment for methanol poisoning
• Massive pyrimethamine and trimethoprim poisoning
CONTRAINDICATIONS
Mechanism of action
Folinic acid is the reduced biologically active form of folic acid and is essential for DNA/
RNA synthesis. Methotrexate acts as an antimetabolite, preventing the reduction of folic
ERRNVPHGLFRVRUJ
acid to folinic acid, by inhibiting dihydrofolate reductase. Administration of exogenous
folinic acid bypasses this inhibition and restores DNA/RNA synthesis. Folates also
enhance the elimination of formate in methanol poisoning.
Pharmacokinetics
Oral bioavailability of folinic acid is almost 100% after a 15-mg dose, but falls with higher
doses. The active isomer has a volume of distribution of 13.6 L and an elimination
half-life of 35 minutes. Elimination is predominantly by metabolism to an active
metabolite, 5-methyltetrahydrofolate, which has a volume of distribution of 40 L and an
elimination half-life of over 400 minutes.
ADMINISTRATION
Methotrexate overdose
• Give 15 mg PO, IM or IV every 6 hours.
• For single acute methotrexate overdose, therapy may be ceased
when methotrexate level is confirmed to be below the threshold
for toxicity (see Table 3.51.2) for an acute single overdose.
It is otherwise continued for at least 3 days or until the serum
methotrexate is <0.05 micromol/L.
• With chronic toxicity, therapy should be continued for at least 3
ANTIDOTES
days and until the serum methotrexate is <0.05 micromol/L.
Methanol poisoning
• Give 2 mg/kg IV every 6 hours.
• Continue until poisoning definitively treated.
423
• Anaphylaxis (rare)
• Seizures (rare)
• Hypercalcaemia with rapid IV administration (>160 mg/minute)
TOXICOLOGY HANDBOOK
Paediatric: dosing for oral methotrexate overdose is not determined
for children.
HANDY TIP
• Folinic acid administration is rarely necessary following acute
single methotrexate overdose.
PITFALL
• Administration of folic acid instead of folinic acid (folic acid is not
an effective antidote for methotrexate toxicity).
CONTROVERSIES
• The indications (if any) for folinic acid administration following
single acute overdose of methotrexate.
— The length of treatment in chronic toxicity is controversial and
should perhaps continue until there is evidence of bone
marrow recovery.
• The value of adjunctive treatment with folinic acid in methanol
poisoning.
ERRNVPHGLFRVRUJ
4.11 FOMEPIZOLE
Alcohol dehydrogenase inhibitor used in management of methanol and
ethylene glycol poisoning. It is not currently registered in either Australia
or New Zealand.
Presentations
Fomepizole 1.5 g/1.5 mL ampoules
Fomepizole sulfate 160 mg/20 mL ampoules (equivalent to 100 mg of fomepizole per
20 mL ampoule)
• Methanol poisoning (confirmed or suspected)
• Ethylene glycol poisoning (confirmed or suspected)
• Note: May be used alone or in combination with haemodialysis.
CONTRAINDICATIONS
ANTIDOTES
• Known hypersensitivity (not yet reported)
Mechanism of action
Fomepizole is a potent competitive inhibitor of alcohol dehydrogenase. It blocks the first
stage in the metabolism of methanol and ethylene glycol to their respective toxic
metabolites. The toxic alcohols are then excreted unchanged in the urine.
Pharmacokinetics
424 Fomepizole has a small volume of distribution (0.7 L/kg). It undergoes hepatic
42
metabolism to form an inactive metabolite, 4-carboxypyrazole. Metabolism is saturable

4
at therapeutic doses. Fomepizole induces its own metabolism when administered for
more than 48 hours, and is dialysable.
TOXICOLOGY HANDBOOK
ADMINISTRATION
• Loading dose: 15 mg/kg in 100 mL of normal saline or 5%
dextrose IV over 30 minutes.
• Maintenance dose: 10 mg/kg in 100 mL of normal saline or 5%
dextrose IV over 30 minutes every 12 hours for 48 hours.
• Note: If administration for more than 48 hours is required,
increase to 15 mg/kg every 12 hours to compensate for induction
of metabolism.
• Monitoring of fomepizole concentrations is not necessary.
• If haemodialysis is undertaken, fomepizole should be given every
4 hours rather than every 12 hours or, alternatively, as a
continuous infusion at 1 mg/kg/hour for the entire duration of
haemodialysis.

• Treatment continues until ethylene glycol or methanol levels are
<30 mg/dL.

• The adverse effect profile is benign. The most common adverse
effect is discomfort at the infusion site. Minor symptoms such as
headache, nausea or dizziness may occur.
ERRNVPHGLFRVRUJ
Pregnancy: safety not established. Ethanol should be considered as
an alternative.
CONTROVERSIES
• The appropriate threshold concentration of ethylene glycol or
methanol at which an alcohol dehydrogenase inhibitor should be
started is not established. The currently recommended
concentration of 20 mg/dL is undoubtedly conservative.
• The superiority of fomepizole over ethanol as an alcohol
dehydrogenase inhibitor. Potential advantages of fomepizole
include ease of administration, more predictable pharmacokinetics,
improved adverse effect profile, easier monitoring of therapy and
potentially reduced need for haemodialysis. The principal
disadvantages are availability and higher cost.
• It remains unclear as to when use of fomepizole might obviate the
need for haemodialysis in methanol poisoning.
ANTIDOTES
References
Barceloux DG, Krenzelok EK, Olson K et al. American Academy of Clinical Toxicology
Practice Guidelines on the Treatment of Ethylene Glycol Poisoning. Journal of
Toxicology – Clinical Toxicology 1999; 37:537–560.
Beatty L, Green K, Magee K, Zed P. A systematic review of ethanol and fomepizole use
in toxic alcohol ingestion. Emergency Medicine International 2013; 2013:638057. 425
Brent J. Fomepizole for ethylene glycol and methanol poisoning. New England Journal of
Medicine 2009; 360:2216–2223.
Brent J, McMartin K, Phillips SP et al. Fomepizole for the treatment of ethylene glycol
TOXICOLOGY HANDBOOK
poisoning. New England Journal of Medicine 1999; 340:832–838.
Brent J, McMartin K, Phillips SP et al. Fomepizole for the treatment of methanol
poisoning. New England Journal of Medicine 2001; 344:424–429.
Lepik KJ, Levy AR, Sobolev BG et al. Adverse drug events associated with the antidotes
for methanol and ethylene glycol poisoning: a comparison of ethanol and
fomepizole. Annals of Emergency Medicine 2009; 53:439–450.
4.12 GLUCOSE
Symptomatic hypoglycaemia resulting from toxic exposures must be
immediately corrected by administration of glucose. In all but the mildest
of cases this is achieved with an intravenous bolus of hypertonic glucose
solution.
Presentations
Glucose 50 g/1000 mL (5% solution) IV infusion packs
Glucose 12.5 g/50 mL (25% solution) IV infusion packs
Glucose 25 g/50 mL (50% solution) single-use syringes
Glucose 100 mg/10 mL (10% solution) ampoules
Glucose 5 g/100 mL (5% solution) vials
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Glucose 5 g/10 mL (50% solution) ampoules
Glucose 25 g/50 mL (50% solution) vials
Glucose 12.5 g/200 mL (5% solution) IV infusion packs
• Correction of hypoglycaemia
— Ethanol ingestion in children
— Insulin poisoning
— Propranolol poisoning
— Quinine poisoning
— Salicylate poisoning
— Sulfonylurea poisoning
— Valproate poisoning
• Combined with high-dose insulin to maintain euglycaemia (see
Chapter 4.14: Insulin (high-dose))
— Beta-blocker poisoning
— Calcium channel poisoning
ANTIDOTES
CONTRAINDICATIONS
• No absolute contraindications
Mechanism of action
Parenteral administration of glucose solutions rapidly corrects hypoglycaemia. However,
426 the effect will be of relatively short duration in hyperinsulinaemic states. When insulin
therapy is used therapeutically to control hyperkalaemia or in the management of
42
calcium channel and beta-blocker toxicity, concomitant administration of dextrose is

6
required to maintain euglycaemia.

TOXICOLOGY HANDBOOK
Pharmacokinetics
Under normal conditions, blood glucose concentration is maintained within a relatively
narrow range by a variety of homeostatic mechanisms. Toxic hypoglycaemia is usually a
result of a hyperinsulinaemic state.
ADMINISTRATION
• Place the patient in a monitored area where equipment and
personnel are available to frequently monitor blood glucose levels
and observe for clinical features of hypoglycaemia.
• Initial correction of symptomatic hypoglycaemia:
— Adult – initial bolus of 50 mL of 50% glucose IV; repeat if no
immediate clinical improvement
— Child – 2 mL/kg bolus of 10% glucose IV; repeat if no
immediate clinical improvement.
• Deliberate self-poisoning with insulin:
— Ongoing glucose infusion will be necessary, as the glucose
requirement may be massive; the infusion rate is titrated to
maintain euglycaemia or mild hyperglycaemia
— Infusion of concentrated solutions (50%) via a central line is
usually necessary to avoid excessive fluid administration and
severe phlebitis.
• Deliberate self-poisoning with sulfonylureas:
— Patients require infusion of large volumes of concentrated
glucose solution, until such time as the hyperinsulinaemic
ERRNVPHGLFRVRUJ
state is controlled by administration of octreotide (see
Chapter 4.19: Octreotide).
• Hypoglycaemia from other causes:
— Usually have a much lower ongoing glucose requirement, e.g.
chronic sulfonylurea poisoning
— Oral supplementation may suffice, but admission to hospital
for careful monitoring of glucose requirement is essential.

• Euglycaemia or mild hyperglycaemia

• Hyperglycaemia
• Hyperosmolality
• Hypokalaemia with large doses in hyperinsulinaemic state
• Local thrombophlebitis from extravasation
• Rebound hypoglycaemia due to further stimulation of insulin
secretion (especially in sulfonylurea overdose)
ANTIDOTES
— Rebound hypoglycaemia mandates further boluses of
concentrated glucose solution IV.
427
HANDY TIPS
• Anticipate the need for large ongoing dextrose requirement
following deliberate self-poisoning with insulin and insert a central
TOXICOLOGY HANDBOOK
line to commence 50% glucose solution.
• Start octreotide after initial correction of hypoglycaemia in a
patient with sulfonylurea overdose.
• Serum potassium replacement is necessary with glucose
infusions.
PITFALLS
• Failure to anticipate ongoing glucose requirement in patient with
deliberate self-poisoning with insulin.
• Failure to start octreotide after initial treatment with glucose in the
patient with deliberate self-poisoning with a sulfonylurea.
4.13 HYDROXOCOBALAMIN
Vitamin B12a
Hydroxocobalamin is a vitamin B12 (cyanocobalamin) precursor. In high
doses, it is an effective chelator of cyanide.
Presentations
Kits containing 2 vials of hydroxocobalamin 2.5 g as lyophilised powder and 2 vials of
100 mL normal saline for reconstitution (Cyanokit®)
Hydroxocobalamin chloride 1 mg/mL ampoules
ERRNVPHGLFRVRUJ
• Known cyanide poisoning with serious clinical effects (altered
mental status, seizures, hypotension, significant lactic acidosis in
context of relatively normal oxygen saturation)
• Suspected cyanide poisoning with serious clinical effects
— It is the preferred cyanide antidote in this situation because of
its relatively benign adverse effects even if administered to a
patient without cyanide poisoning.
CONTRAINDICATIONS
Mechanism of action
Hydroxocobalamin has a complex molecular structure with a cobalt ion bound to a
hydroxyl group at its centre. As do other cobalt-containing compounds, it has a high
affinity for cyanide. Cyanide binds to the central cobalt ion and displaces the hydroxyl
group, forming cyanocobalamin, which is relatively non-toxic even in high concentrations
and is excreted in the urine. Hydroxocobalamin prevents circulating cyanide from
ANTIDOTES
entering tissues and binding to cytochrome oxidase and also promotes reactivation of
inhibited cytochrome oxidase by removing cyanide.
Pharmacokinetics
Hydroxocobalamin has a small volume of distribution of 0.1–0.5 L/kg. It is largely
excreted unchanged in the urine with an elimination half-life from 1.5 to 26 hours.
Cyanocobalamin is also excreted in the urine, with an elimination half-life of
approximately 9 hours in cyanide-poisoned patients treated with hydroxocobalamin.
428
42
ADMINISTRATION
8

TOXICOLOGY HANDBOOK

• Reconstitute hydroxocobalamin 2.5 g (1 ampoule) with 100 mL
normal saline provided in the kit. Administer reconstituted solution
IV over 15 minutes.
• Repeat the process with second vial in the kit to give a total dose
of 5 g.
• This dose should be sufficient to bind 100 mg of cyanide;
however, if the ingested dose is known to be greater than this, a
larger initial dose could be administered.
• If there is no improvement within 15 minutes, repeat
administration of hydroxocobalamin or administration of sodium
thiosulfate should be considered.


• Minor hypertension, bradycardia and tachycardia have been
occasionally reported; none required treatment and all resolved
within 48 hours.
• Orange-red discolouration of the skin, mucous membranes, urine,
plasma and other bodily fluids occurs and lasts for 12–48 hours,
but is not consequential.
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• Acute allergic reactions have not been reported following single
high-dose therapy in poisoned patients.
Paediatric: the paediatric dose has not been determined, but it is
reasonable to commence with 50 mg/kg.
HANDY TIPS
• Only the Cyanokit® provides a dose of hydroxocobalamin
sufficient to treat cyanide poisoning. It is expensive, not widely
available and only available in Australia if imported under the
Special Access Scheme. The alternative preparation, used to treat
pernicious anaemia, contains only 1 mg of hydroxocobalamin.
5000 ampoules and a volume of 5 L would be necessary to
obtain the dose necessary to treat one case of cyanide poisoning.
• Hydroxocobalamin 5 g IV should be given to patients in cardiac
arrest from cyanide poisoning while resuscitation efforts continue.
ANTIDOTES
• Failure to improve after the first dose of hydroxocobalamin
prompts reconsideration of the diagnosis in suspected cyanide
poisoning.
• Hydroxocobalamin and sodium thiosulfate must not be mixed in
the same infusion, as hydroxocobalamin complexes will result.
• The discolouration of bodily fluids that occurs may interfere with
laboratory analyses that use colorimetric methods, including liver 429
enzymes, bilirubin, creatinine, creatine kinase, phosphorus,
glucose, magnesium and iron. Falsely high or falsely low results
may be obtained, but are rarely of clinical significance.
TOXICOLOGY HANDBOOK
PITFALLS
• Failure to stock the appropriate preparation.
• Failure to administer an adequate dose.
CONTROVERSIES
• This expensive antidote (approximately A$2000 per pack of 2
ampoules) is rarely required but must be immediately available if it
is to be useful. It is only appropriate to stock in locations where
there is a risk of being confronted with a case of cyanide
poisoning.
• Relative efficacy of hydroxocobalamin compared with supportive
care and with other cyanide antidotes.
• It has previously been advocated that administration of
hydroxocobalamin should be followed by administration of
sodium thiosulfate 12.5 g (50 mL of 25% solution) IV over 10
minutes. This is probably unnecessary.
References
Borron SW, Baud FJ, Megarbane B et al. Hydroxocobalamin for severe acute cyanide
poisoning by ingestion or inhalation. American Journal of Emergency Medicine 2007;
25:551–558.
Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric
treatment of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813.
ERRNVPHGLFRVRUJ
Thompson JP, Marrs TC. Hydroxocobalamin in cyanide poisoning. Clinical Toxicology
2012; 50:875–885.
4.14 INSULIN (high-dose)

High-dose insulin (HDI) therapy produces a significant inotropic response
in severe calcium channel blocker overdose.
• Calcium channel blocker (CCB) poisoning with haemodynamic
compromise
• Beta-blocker poisoning with haemodynamic compromise
CONTRAINDICATIONS
• None
ANTIDOTES
Mechanism of action
Insulin has a well-established inotropic effect in the failing heart. It is thought to be due
to its ability to increase lactate oxidation while at the same time completely eliminating
myocardial fatty acid oxidation. This metabolic profile optimises heart function under
stress conditions. Glucose is given simultaneously with insulin to maintain euglycaemia.
HDI produces increased inotropy, increased intracellular glucose transport and vascular
430 dilation. It does not act as a vasopressor.
43
0
ADMINISTRATION
• This antidote is only administered to critically ill patients fully
TOXICOLOGY HANDBOOK
monitored in a critical care setting. Careful attention to blood

glucose and serum potassium concentrations must be maintained
during therapy.
• Commence therapy by administering:
— Glucose 25 g (50 mL of 50% solution) IV bolus, then
— Short-acting insulin 1 IU/kg IV bolus.
• Continue therapy with:
— Glucose 25 g/hour IV infusion via a central line
— Short-acting insulin 0.5 IU/kg/hour IV infusion.
• The glucose infusion is titrated to maintain euglycaemia.
• The insulin infusion may be increased to 1–2 IU/kg/hour or even
greater if required.
• The combined infusions should continue for as long as the patient
has cardiovascular instability.

• Therapy is weaned as cardiovascular toxicity resolves.

• Hypoglycaemia
— Dextrose infusion is titrated to maintain euglycaemia.
— Bedside BGL should be checked every 10 minutes during
initiation and titration of insulin.
— BGL should be checked every 30–60 minutes once the insulin
dose is stable.
ERRNVPHGLFRVRUJ
• Hypokalaemia, hypomagnesaemia, hypophosphataemia
— Potassium supplementation may be required. Aim to maintain
serum potassium concentration in the range of
3.0–3.5 mmol/L as the total body stores are not depleted, and
potassium will shift back to the extracellular compartments
once insulin is discontinued.
— Serum potassium concentration should be checked every 1
hour during initiation and titration of insulin.
— Serum potassium concentration should be checked every 6
hours once insulin dose is stable.
HANDY TIPS
• HDI is most successful if commenced as soon as haemodynamic
compromise manifests rather than waiting for poor response to
ANTIDOTES
other measures.
• Peak inotropic response is usually observed within 1 hour of
initiation of therapy.
• Glucose supplementation may be required for up to 24 hours
following withdrawal of HDI.
PITFALL 431
• Failure to initiate therapy sufficiently early in life-threatening CCB
or beta-blocker toxicity.
TOXICOLOGY HANDBOOK
CONTROVERSIES
• The use of HDI in severe CCB and beta-blocker poisoning is
supported by experimental evidence and case reports. There are
no clinical trials comparing the use of HDI to other treatments in
humans.
• More aggressive administration regimens have been proposed
and used successfully. One such protocol advocates initiating a
1 IU/kg continuous infusion after a 1 IU/kg bolus and then
increasing the infusion by 2 IU/kg/hour every 10 minutes to a
maximum of 10 IU/kg/hour if no increase in cardiac output or
clinical improvement is observed.
• HDI has been advocated in other toxin-induced shock states but
clinical experience is limited.
References
Engebretsen KM, Kaczmarek KM, Morgan J, Holger JS. High-dose insulin therapy in
beta-blocker and calcium channel-blocker poisoning. Clinical Toxicology 2011;
49:277–283.
Lheureux PE, Zahir S, Gris M et al. Bench-to-bedside review: hyperinsulinaemia/
euglycaemia therapy in the management of overdose of calcium-channel blockers.
Critical Care 2006; 10:212.
Megarbane B, Karyo S, Baud FJ. The role of insulin and glucose (hyperinsulinaemia/
euglycaemia) therapy in acute calcium channel antagonist and beta-blocker
poisoning. Toxicological Reviews 2004; 23(4):215–222.
Yuan TH, Kerns WP, Tomaszewski CA et al. Insulin–glucose as adjunctive therapy for
severe calcium channel antagonist poisoning. Journal of Toxicology – Clinical
Toxicology 1999; 37(4):463–474.
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4.15 INTRAVENOUS LIPID EMULSION
Intravenous lipid emulsion (IVLE) is a sterile emulsion of soya bean oil in
water, used in parenteral nutrition. It is a novel antidote that requires
further study, but may have a role to play in the resuscitation of patients
with refractory cardiac instability or arrest induced by local anaesthetics
or other lipophilic agents.
Presentations
Intravenous lipid emulsion 10%, 500 mL
• Local anaesthetic-induced cardiovascular collapse, resistant to
standard resuscitation protocols
• Possibly considered as a rescue therapy for refractory cardiac
ANTIDOTES
instability or arrest in the context of acute poisoning with other

highly lipid soluble agents, including propranolol, tricyclic
antidepressants and verapamil
CONTRAINDICATIONS
432
• Inadequate standard resuscitative efforts
• Hypersensitivity to egg, soya or peanut protein
43
2
Mechanism of action
Proposed mechanisms include introduction of an intravascular lipid phase that extracts
TOXICOLOGY HANDBOOK
agent from tissue binding sites, increased myocardial ATP synthesis due to reversal of
inhibition of fatty acid delivery to mitochondria and restoration of myocyte function by
activation of calcium and potassium channels and an increase in intracellular calcium.
ADMINISTRATION
• Continue standard resuscitation protocols during administration.
• Give 1–1.5 mL/kg IVLE 20% as IV bolus over 1 minute
• Repeat bolus once or twice at 3–5 minute intervals if required
then
• Infuse IVLE 0.25 mL/kg/minute until haemodynamic stability is
restored.
• Increase to 0.5 mL/kg/minute if hypotension persists.
• Increasing the total dose above 8 mL/kg is unlikely to be beneficial.

• Return of spontaneous circulation with stabilisation of
haemodynamic parameters. Infusion may be restarted if
hypotension recurs on cessation.

• Immediate: allergy and anaphylaxis.
• Pulmonary hypertension, acute lung injury, haematuria,
hypertriglyceridaemia and pancreatitis have been described.
Management is supportive.
ERRNVPHGLFRVRUJ
Paediatric: there are no reports of paediatric administration, but
administration should not be withheld if clinically indicated.
HANDY TIP
• A suitable dosing regimen of IVLE 20% for resuscitating a 70-kg
adult would be an IV bolus of 100 mL followed by an infusion of
400 mL over 20 minutes while continuing advanced life support. If
no response, repeat boluses twice more while giving further
adrenaline. If hypotension persists, increase infusion rate to
400 mL over 10 minutes.
CONTROVERSIES
• Optimum dose and dosing regimen of IVLE are yet to be
established.
•
ANTIDOTES
Short- and long-term adverse effects of IVLE require further study.
• Role of IVLE in poisoning other than that by local anaesthetic
agents requires further study.
— There are numerous reports of IVLE in poisoned patients with
altered mental status. The benefits are questionable and
unlikely to justify potential adverse reactions and distraction of
staff from the priorities of resuscitation and airway support.
433
References
Felice KL, Schumann HM. Intravenous lipid emulsion for local anaesthetic toxicity: a
TOXICOLOGY HANDBOOK
review of the literature. Journal of Medical Toxicology 2008; 4(3):184–191.
Levine M, Skolnik AB, Ruha A-M et al. Complications following antidotal use of
intravenous lipid emulsion therapy. Journal of Medical Toxicology 2014; 10:10–14.
The Association of Anaesthetists of Great Britain and Ireland. Guidelines for the
management of severe local anaesthetic toxicity. August 2007; Available at:
http://www.aagbi.org.
Turner-Lawrence DE, Kerns W. Intravenous fat emulsion: a potential novel antidote.
Journal of Medical Toxicology 2008; 4(2):109–114.
Weinberg G. Lipid rescue resuscitation from local anaesthetic cardiac toxicity.
4.16 METHYLENE BLUE

Methylene blue is the treatment of choice for symptomatic drug-induced
methaemoglobinaemia. It has also been proposed as a potential adjunct
in the treatment of shock states.
Presentations
Methylene blue trihydrate 50 mg/5 mL ampoules
• Symptomatic drug-induced methaemoglobinaemia (signs of
hypoxaemia with chest pain, dyspnoea or confusion).
• Consider in asymptomatic patients with methaemoglobin (MetHb)
levels >20%.
ERRNVPHGLFRVRUJ
• Methylene blue has also been used in anaphylactic and toxic
shock states where hypotension persists despite vasopressor
administration.
CONTRAINDICATIONS
• G6PD deficiency: lack of NADPH in this condition causes
methylene blue to be ineffective, as it cannot be reduced to
leucomethylene blue. Haemolysis may also occur.
• Renal impairment: dose needs to be reduced.
• Methaemoglobinaemia reductase deficiency.
• Nitrite-induced methaemoglobinaemia following the treatment of
cyanide poisoning.
• Hypersensitivity.
Mechanism of action
Methylene blue dramatically increases the natural rate of reduction of MetHb to
haemoglobin. Methylene blue is reduced to leucomethylene blue by methaemoglobin
reductase in the presence of NADPH. Leucomethylene blue then reduces MetHb to
haemoglobin.
ANTIDOTES
Methylene blue inhibits nitric oxide synthase and guanylate cyclase and scavenges
endothelial nitric oxide. In shock states, it appears to have both vasoconstrictive and
positive inotropic effects.
Pharmacokinetics
Methylene blue is rapidly reduced to leucomethylene blue, which is then largely excreted
in the urine as a salt complex.
434
43
ADMINISTRATION
4
• Administer 1–2 mg/kg (0.1–0.2 mL/kg of 1% solution) IV slowly

over 5 minutes. Follow with a normal saline flush to minimise
TOXICOLOGY HANDBOOK
venous irritation.
• MetHb levels should be measured hourly until a consistent fall is
documented.
• Methaemoglobinaemia usually responds to a single dose.
However, a further dose of 1–2 mg/kg may be repeated after
30–60 minutes if the initial response is inadequate.
• In rare instances, such as dapsone poisoning, when
methaemoglobin formation may continue for days, repeat dosing
every 6–8 hours may be necessary for several days.
• A single dose of 1–2 mg/kg has been suggested as adjunctive
therapy in toxic shock states.

• Resolution of symptoms of hypoxaemia.
• Response is confirmed by repeat MetHb estimations.
• Stabilisation of haemodynamic parameters.

• Local pain and irritation commonly occur at site of administration
and extravasation can result in local tissue necrosis.
• Common non-specific adverse effects include headache,
dizziness, restlessness, nausea, vomiting, chest discomfort and
shortness of breath.
• Blue staining of mucous membranes (may mimic cyanosis) and urine.
ERRNVPHGLFRVRUJ
• Methylene blue may paradoxically cause methaemoglobinaemia
when given in high doses (>7 mg/kg) secondary to a direct
oxidative effect on haemoglobin.
• Acute haemolytic anaemia may occur in G6PD-deficient
individuals and with very large doses of methylene blue
(>15 mg/kg).
Pregnancy: no restrictions on use.
Lactation: no restrictions on use.
Paediatric: Initial paediatric dose is 1 mg/kg.
HANDY TIPS
• Patients with preexisting conditions that interfere with
oxygenation, such as anaemia or coronary artery disease, may
require methylene blue administration at MetHb concentrations as
low as 10%.
• Pulse oximetry is unreliable, as MetHb and methylene blue
ANTIDOTES
interfere with the readings.
• Replacement of the blue discolouration of methaemoglobinaemia
with that of methylene blue means that this clinical sign is an
unreliable guide to response to therapy.
• Consider the following problems if MetHb levels are not falling
after 2 doses of methylene blue:
— Massive ongoing exposure to oxidising agent 435
— Sulfhaemoglobinaemia (e.g. by sulfonamides)
— G6PD deficiency
— Methaemoglobin reductase deficiency
TOXICOLOGY HANDBOOK
— Abnormal haemoglobin
— Excessive methylene blue.
• If methylene blue fails to control methaemoglobinaemia, consider
exchange transfusion or hyperbaric oxygen therapy.
CONTROVERSIES
• Whether a certain MetHb concentration mandates methylene blue
treatment. Most clinicians continue to monitor asymptomatic
patients with elevated levels even >20% and do not treat unless
symptoms of hypoxaemia develop.
• Role, indications and dosing of methylene blue in refractory toxic
shock states require further study.
References
Clifton J, Leiken JB. Methylene blue. American Journal of Therapeutics 2003;
10:289–291.
Lo JCY, Darracq MA, Clark RF. A review of methylene blue treatment for cardiovascular
collapse. The Journal of Emergency medicine 2014; 46:670–679.
4.17 N-ACETYLCYSTEINE
N-acetylcysteine (NAC) is the most widely used sulfhydryl donor in the
treatment of paracetamol poisoning. Standard therapy consists of a
ERRNVPHGLFRVRUJ
series of three infusions given over 20 hours. It is almost completely
protective against paracetamol-induced hepatotoxicity when
administered within 8 hours of an overdose. Adverse effects are limited
to mild anaphylactoid reactions.
Presentations
200 mg/mL injectable (10 mL, 30 mL)
• Acute paracetamol overdose
• Repeated supratherapeutic paracetamol ingestion
• Paracetamol-induced fulminant hepatic failure
• Note: NAC is indicated in the above situations where there is
judged to be a risk of hepatotoxicity. Risk assessment is based
on dose ingested, serum paracetamol and hepatic transaminase
levels, and is discussed in detail in Chapter 3.60: Paracetamol:
Acute overdose, Chapter 3.61: Paracetamol: Modified-release
preparations and Chapter 3.62: Paracetamol: Repeated
ANTIDOTES
supratherapeutic ingestion
• NAC has been investigated for use in poisonings by a variety of
other agents, including chemotherapeutic agents, paraquat,
carbon tetrachloride, chloroform, acrylonitrile, cyclophosphamide
and amanita mushrooms
CONTRAINDICATIONS
436
• None
43
6
Mechanism of action
NAC prevents N-acetyl-p-benzoparaquinone imine (NAPQI)-induced hepatotoxicity when
TOXICOLOGY HANDBOOK
given within 8 hours of an acute paracetamol overdose. It ameliorates the clinical course
of toxicity when given after that time or following repeated supratherapeutic ingestion.
Four possible mechanisms may contribute to this action:
1 Increased glutathione availability
2 Direct binding to NAPQI
3 Provision of inorganic sulfate
4 Reduction of NAPQI back to paracetamol.
The antioxidant properties of NAC may offer benefit in a number of other poisonings
in which oxidative stress is an important toxic mechanism and may also explain its
beneficial effects in liver failure of any cause.
Pharmacokinetics
NAC metabolism is complex, with a variety of sulfur-containing compounds being
produced. Plasma half-life following IV administration is 6 hours and 30% is eliminated
unchanged in the urine.
ADMINISTRATION
• Patients are carefully monitored for anaphylactoid reaction during
and after the initial dose of NAC. Cardiac monitoring is not
required after that time.
• Give 150 mg/kg (0.75 mL/kg) NAC diluted in 200 mL of 5%
dextrose IV over 15 minutes
followed by
• 50 mg/kg (0.25 mL/kg) NAC diluted in 500 mL of 5% dextrose IV
over 4 hours
ERRNVPHGLFRVRUJ
followed by
• 100 mg/kg (0.5 mL/kg) NAC diluted in 1000 mL of 5% dextrose IV
over 16 hours.
• The standard treatment duration is 20.25 hours; however, it may be
interrupted before this time where risk of hepatotoxicity is excluded.
• The infusion may be continued beyond 20 hours in patients with
late presentation, repeated supratherapeutic ingestion or
biochemical evidence of hepatotoxicity. Repeat the final dose of
100 mg/kg NAC diluted in 1000 mL of 5% dextrose IV over 16
hours until such time as transaminases begin to fall and the
patient is improving clinically.

• Absent or resolving hepatotoxicity as determined by transaminases

• Anaphylactoid reactions (incidence of 10–50%), including
hypotension, flushing, rash and angio-oedema
ANTIDOTES
— These usually occur during or shortly after the initial dose and
can be treated with an oral H1-blocker (e.g. loratadine 10 mg
PO) or promethazine 12.5 mg IV.
— The infusion need only be ceased if the reaction is severe, in
which case it may be restarted as soon as the reaction is
settling.
SPECIFIC CONSIDERATIONS 437

Pregnancy: NAC crosses the placenta. When indicated, it is
beneficial for both mother and fetus.
TOXICOLOGY HANDBOOK
Paediatric: the dose of NAC is the same as for adults. However, it
should be infused in smaller volumes of 5% dextrose (use 0.45%
sodium chloride with 5% dextrose if there are concerns about
hyponatraemia).
• Children <20 kg body weight:
— 150 mg/kg in 3 mL/kg of 5% dextrose over 15 minutes
followed by
— 50 mg/kg in 7 mL/kg of 5% dextrose over 4 hours
followed by
— 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours
followed by
— 50 mg/kg in 7 mL/kg of 5% dextrose over 8 hours.
• Children >20 kg body weight:
— 150 mg/kg in 100 mL of 5% dextrose over 15 minutes
followed by
— 50 mg/kg in 250 mL of 5% dextrose over 4 hours
followed by
— 50 mg/kg in 250 mL of 5% dextrose over 8 hours
followed by
— 50 mg/kg in 250 mL of 5% dextrose over 8 hours.
HANDY TIP
• Always chart NAC infusions using the chart supplied in the
package insert, which describes NAC volume rather than
milligrams. This practice reduces the chance of a dosing error.
ERRNVPHGLFRVRUJ
PITFALLS
• Failure to initiate NAC empirically in the patient who presents
more than 8 hours following a paracetamol overdose of
>200 mg/kg.
• Failure to warn patient and staff of the high likelihood of a mild
anaphylactoid reaction occurring early in treatment.
CONTROVERSIES
• The practice of giving the initial dose of NAC over 60 minutes
rather than 15 minutes does not appear to significantly reduce the
incidence of anaphylactoid reactions.
• The value of NAC in patients who present more than 24 hours
post overdose with elevated transaminases, but who are
otherwise well.
• The optimal regimen for administration of NAC is not defined.
Multiple protocols now exist including a number of protocols of
shorter duration.
• Use of increased concentrations and prolonged infusions of NAC
ANTIDOTES
have been advocated following massive (>500 mg/kg)

paracetamol overdose or the ingestion of modified release
presentations.
References
Bateman DN, Dear JW, Thanacoody HR et al. Reduction of adverse effects from
438 intravenous acetylcysteine treatment for paracetamol poisoning: a randomized
43
8
poisoning in Australia and New Zealand – explanation and elaboration. A consensus
TOXICOLOGY HANDBOOK
statement from clinical toxicologists consulting to the Australasian poisons

information centres. Medical Journal of Australia 2008; 188:296–301.
Kerr F, Dawson A, Whyte IM et al. The Australasian Clinical Toxicology Investigators
Collaboration randomized trial of different loading infusion rates of N-acetylcysteine.
Annals of Emergency Medicine 2005; 45:409–413.
Prescott LF, Illingworth RN, Critchley JA. Intravenous N-acetylcysteine: the treatment of
choice for paracetamol poisoning. British Medical Journal 1979; 2:1097.
Rumack BH, Bateman DH. Acetaminophen and acetylcysteine dose and duration: past,
present and future. Clinical Toxicology 2012; 50:91–98.
4.18 NALOXONE
This opioid antagonist is a useful adjunct in the management of opioid
intoxication.
Presentations
Naloxone hydrochloride 400 microgram/1 mL ampoules
Naloxone hydrochloride 800 microgram/2 mL pre-filled syringe
Naloxone hydrochloride 2 mg/5 mL pre-filled syringe
• Reversal of CNS and respiratory depression caused by opioid
intoxication
• Empirical treatment for coma thought to be secondary to opioids
ERRNVPHGLFRVRUJ
CONTRAINDICATIONS
• Avoid in the opioid-dependent individual unless:
— Significant respiratory depression (respiratory rate <8) or
hypoxia
or
— Significant CNS depression (GCS <12)
Mechanism of action
Naloxone is a pure competitive opioid antagonist at mu, kappa and delta receptors. It
reverses opioid effects, including sedation, respiratory depression and hypoxia.
Pharmacokinetics
Naloxone has poor oral bioavailability with extensive first-pass effect. It is well absorbed
after IM, SC or endotracheal administration. Distribution and onset of action are rapid
after IV or IM administration. It is metabolised by the liver, with an elimination half-life of
60–90 minutes. Duration of effect also depends on dose and rate of elimination of
agonist, but is usually from 20 to 90 minutes.
ADMINISTRATION
ANTIDOTES
Carefully monitor respiratory rate, GCS and oxygen saturation in
an effort to detect re-sedation.
• Treatment dose is extremely variable and depends on the amount
and type of agonist present.
• Give an initial bolus dose of 100 micrograms IV or 400 micrograms 439
IM or SC if IV access cannot be established. Larger initial doses
may safely be used where the patient is not opioid dependent.
• Repeated doses of 100 micrograms IV every 30–60 seconds may
TOXICOLOGY HANDBOOK
be given until adequate spontaneous respiration is reestablished.
• Doses >400 micrograms are rarely required following heroin
overdose; however, larger doses may be required in overdose
from partial opioid antagonists.
• Duration of treatment is extremely variable and dependent on the
absorption and elimination kinetics of the ingested competing
agonist. Clinically significant re-sedation is extremely unusual
following heroin overdose. However, following overdose with
controlled-release morphine, oxycodone or methadone,
re-sedation is expected and a naloxone infusion may be necessary.
• Commence the naloxone infusion rate at 2 3 of the initial dose
required/hour. Administration of 100 microgram/hour can be
obtained by diluting 2 mg of naloxone in 100 mL normal saline
and running at 5 mL/hour.
• Monitor the patient for evidence of opioid withdrawal and titrate
the infusion according to clinical response.

• In the non-opioid dependent individual, naloxone may be given in
a dose sufficient to achieve and maintain a normal mental status.
• In the opioid-dependent individual, naloxone dose should be
sufficient to permit maintenance of an adequate airway and
respiratory rate and produce a patient who is rousable (GCS
13–14), but not achieve full reversal.
ERRNVPHGLFRVRUJ
• All patients given naloxone should be observed for re-sedation for
at least 2 hours after the last dose.

• In non-opioid dependent individuals, naloxone is without
significant adverse effects, even in very large doses.
• In opioid-tolerant patients, dose-dependent production of a
withdrawal syndrome occurs. This can include severe agitation
and aggression and should be avoided.
• If a withdrawal syndrome is inadvertently produced, immediately
cease further administration of naloxone. Physical and chemical
control of the disturbed patient may be necessary if reassurance
fails. Avoid long-acting chemical sedation as the duration of
naloxone-induced withdrawal is short (usually <90 minutes).
withheld if clinically indicated. Maternal opioid dependence is
ANTIDOTES
associated with fetal opioid dependence. Naloxone crosses the

placenta and precipitation of opioid withdrawal in the mother will be
associated with precipitation of opioid withdrawal in the fetus and
should be avoided.
Paediatric: naloxone can usually be given with impunity to suspected
cases of paediatric opioid intoxication, as children are unlikely to be
440 opioid-dependent. Give a 400-microgram bolus IV to exclude or
confirm the diagnosis of opioid intoxication.
44
0
HANDY TIPS
TOXICOLOGY HANDBOOK
• Do not completely reverse opioid intoxication in opioid-dependent

patients, as withdrawal will render assessment and management
more difficult.
• IV administration is superior to IM or SC as it allows titration of
dose.
• Anticipate the need for ongoing naloxone administration following
overdose of methadone, oxycodone or controlled-release oral
morphine.
• Monitor patients on naloxone infusion for both re-sedation and
withdrawal and adjust the rate of infusion accordingly.
PITFALLS
• Production of severe acute withdrawal syndrome in opioid-
dependent patients.
• Failure to detect and correct re-sedation following initial response
to naloxone.
• Inadequate naloxone dose following partial agonist overdose.
CONTROVERSIES
• Intranasal or nebulised naloxone may be useful, but these routes of
administration are not yet validated and cannot be recommended.
• Naloxone has been advocated in the management of clonidine,
alcohol, benzodiazepine and sodium valproate intoxication. It
does not appear to be clinically useful in these situations.
ERRNVPHGLFRVRUJ
References
Ashton H, Hassan Z. Best evidence topic report: intranasal naloxone in suspected opioid
overdose. Emergency Medicine Journal 2006; 23:221–223.
Clarke SFJ, Dargan PI, Jones AL. Naloxone in opioid poisoning: walking the tightrope.
Emergency Medicine Journal 2005; 22:612–616.
4.19 OCTREOTIDE
Long-acting synthetic octapeptide analogue of somatostatin useful in the
control of sulfonylurea-induced hypoglycaemia.
Presentations
Octreotide 50 microgram/mL injectable (1 mL)
Octreotide 10 mg injectable (powder and solvent)
ANTIDOTES
• Drug-induced hyperinsulinaemic states resulting in persistent
hypoglycaemia (blood glucose <4 mmol/L) including:
— Intentional sulfonylurea overdose
— Therapeutic sulfonylurea-induced hypoglycaemia
— Quinine-induced hypoglycaemia 441
CONTRAINDICATIONS
•
TOXICOLOGY HANDBOOK
None
Mechanism of action
Octreotide powerfully suppresses endogenous insulin release from pancreatic islet cells.
Pharmacokinetics
Octreotide has a bioavailability following SC administration of 100%. Peak levels are
achieved within 30 minutes, but are only half those achieved following IV administration.
About 30% is excreted unchanged by the kidney, with an elimination half-life of 90
minutes.
ADMINISTRATION
• Place the patient in a monitored area where equipment and
personnel are available to frequently monitor blood glucose levels
and observe for clinical features of hypoglycaemia.
• Administer an initial bolus of 50 micrograms IV.
• Commence a continuous infusion at 25 microgram/hour by
diluting 500 micrograms of octreotide in 500 mL of normal saline
and running at 25 mL/hour.
• An alternative to IV infusion is 100 micrograms SC or IM every 6
hours. Breakthrough hypoglycaemia may occur between doses.
• Normoglycaemia without glucose supplementation is usually
maintained on the octreotide infusion. If hypoglycaemia recurs, it
should be corrected with 50% dextrose and the infusion rate
doubled.
ERRNVPHGLFRVRUJ
• Normoglycaemia must be maintained for 12 hours off octreotide
and on a normal diet before the patient is medically cleared.

• Minor nausea only
Pregnancy: safety is not established. Administration should not be
Paediatric: the optimal dose in children is unknown. Given the
absence of significant adverse effects, commence therapy with an
initial bolus of 1 microgram/kg IV or SC followed by an intravenous
infusion of 1 microgram/kg/hour.
HANDY TIPS
• Initiation of therapy with a bolus of 100 micrograms SC is useful
ANTIDOTES
in stabilising a patient in a remote location prior to transfer to the

place of definitive care. This dose may be brought in by a retrieval
team if unavailable on site.
• If plasma insulin levels are available they can usefully assist in the
withdrawal of octreotide. A plasma insulin level in the normal
range at 6 hours after cessation of the octreotide infusion allows
the patient to be medically cleared.
442
44
2
PITFALL
• Failure to start therapy when hypoglycaemia first develops
TOXICOLOGY HANDBOOK
following sulfonylurea overdose.
CONTROVERSIES
• Intravenous versus subcutaneous administration and optimal
dosing regimens.
• Role of octreotide in the management of therapeutic sulfonylurea-
induced hypoglycaemia.
References
Boyle PJ, Justice K, Krentz AJ et al. Octreotide reverses hyperinsulinemia and prevents
hypoglycaemia induced by sulfonylurea overdoses. Journal of Clinical Endocrinology
and Metabolism 1993; 77:752–756.
Fasano CJ, O’Malley G, Dominici P et al. Comparison of octreotide and standard therapy
versus standard therapy alone for the treatment of sulfonylurea-induced
hypoglycemia. Annals of Emergency Medicine 2008; 51:400–406.
Glatstein M, Scolnik D, Bentur Y. Octreotide for the treatment of sulfonylurea poisoning.
McLaughlin SA, Crandall CS, McKinney PE. Octreotide: an antidote for sulfonylurea
induced hypoglycaemia. Annals of Emergency Medicine 2000; 36:133–138.
4.20 PENICILLAMINE
Potent oral chelating agent for a broad range of heavy metals. Agent of
choice in very few scenarios due to poor side-effect profile and the
existence of better tolerated and more efficacious agents.
ERRNVPHGLFRVRUJ
Presentations
Penicillamine 125 mg tablets (100)
Penicillamine 250 mg tablets (100)
• Copper toxicity (Wilson’s disease)
• Second-line drug for chelation of other heavy metals, including
arsenic, iron, lead, mercury and zinc
CONTRAINDICATIONS
• Penicillin allergy
• Pregnancy
• Renal failure (unable to excrete chelates)
Mechanism of action
Penicillamine is an orally administered chelating agent. It is a penicillin derivative without
antibiotic activity. It binds to heavy metals with varying degrees of efficacy. The
penicillamine–metal chelate is soluble and eliminated by renal excretion.
ANTIDOTES
Pharmacokinetics
Penicillamine is well absorbed following oral administration, with peak concentrations
occurring within hours. It is distributed throughout the body water. Elimination is urinary
mainly as sulfide conjugates. Elimination half-life is up to 90 hours.
ADMINISTRATION
• Administer 4–7 mg/kg orally four times a day. 443
• Maximum adult daily dose is 2 g.
• Monitor closely for adverse effects:
— Second weekly full blood count and urinalysis
TOXICOLOGY HANDBOOK
— Weekly urine and/or blood testing for target heavy metal.
• Commencing therapy in the lower dose range may minimise
adverse effects.
• Duration of therapy depends upon ability to tolerate the antidote
and the rate of elimination of the target metal. Months of therapy
may be required.

• Blood metal concentrations in desired range

• Drug reactions are multiple and frequent, especially in the higher
dose range. They are commonly responsible for cessation of
therapy and include:
— Cutaneous hypersensitivity: erythematous skin reactions
— Systemic hypersensitivity: fever, proteinuria, haematuria,
erythema multiforme
— Haematological: bone marrow hypoplasia with varying degrees
of thrombocytopenia, leucopenia and fatal agranulocytosis
— Neurological: myasthenia gravis, peripheral neuropathy
— Nephrotoxicity: nephrotic syndrome, glomerulonephritis
— Other: Goodpasture’s syndrome, hepatotoxicity, pancreatitis.
• Therapy should be ceased if significant cutaneous reactions,
abnormal urinalysis or falling white cell or platelet counts occur.
ERRNVPHGLFRVRUJ
Pregnancy: this drug is teratogenic and is avoided in pregnancy.
Paediatrics: dose as for adults. Lower doses will minimise adverse
effects.
HANDY TIP
• Should only be prescribed by clinicians experienced with its use
and adverse effects.
CONTROVERSY
• Lower dose regimens may achieve comparable clinical efficacy
with improved adverse effect profile.
References
Liebelt EL, Shannon MW. Oral chelators for childhood lead poisoning. Pediatric Annals
1994; 23(11):616–619, 623–626.
Shannon MW, Townsend MK. Adverse effects of reduced-dose d-penicillamine in
ANTIDOTES
children with mild-to-moderate lead poisoning. Annals of Pharmacotherapy 2000;

34(1):15–18.
4.21 PHYSOSTIGMINE
A reversible acetylcholinesterase inhibitor useful in the treatment of
444 central anticholinergic delirium.
44
4
Presentations
Physostigmine 1 mg/2 mL ampoules
TOXICOLOGY HANDBOOK
• Central antimuscarinic manifestations (agitated delirium) not easily
controlled with benzodiazepine sedation
• Isolated anticholinergic agent poisoning (i.e. atropine, benztropine)
CONTRAINDICATIONS
• Bradydysrhythmias
• Intraventricular block (QRS >100 ms)
• AV block
• Bronchospasm
Mechanism of action
Physostigmine is a carbamate with a tertiary amine structure. It produces reversible
inhibition of acetylcholinesterase and accumulation of acetylcholine. The increased
concentration of acetylcholine overcomes the postsynaptic muscarinic receptor blockade
produced by anticholinergic agents.
Pharmacokinetics
Physostigmine is very poorly absorbed after oral administration. It is able to cross the
blood–brain barrier. It is rapidly metabolised by cholinesterase, with an elimination
half-life of about 20 minutes.
ADMINISTRATION
ERRNVPHGLFRVRUJ
• Confirm absence of conduction defects on 12-lead ECG.
• Administer 0.5–1 mg as a slow IV push over 5 minutes and repeat
every 10 minutes until the desired clinical effect is observed.
• It is rare for a total dose of more than 4 mg to be required.
• The duration of action of physostigmine is much shorter than
most cases of anticholinergic delirium, and delirium may reoccur
1–4 hours following initial clinical response. Further carefully
titrated doses may then be given.

• Resolution of delirium

• Excessive doses of physostigmine produce clinical features of
cholinergic stimulation including:
— Seizures, usually seen following rapid administration
— Bradycardia, variable degrees of heart block
— Bronchospasm, bronchorrhoea, nausea, vomiting and diarrhoea.
ANTIDOTES
• The cholinergic manifestations of physostigmine overdose should
be managed with good supportive care and, if necessary,
administration of titrated doses of atropine until there is resolution
of bradycardia and drying of respiratory secretions.
• Physostigmine may also prolong the effect of suxamethonium or
inhibit the action of non-depolarising neuromuscular blockers.
445
Pregnancy: safety not established. Alternative agents should be
considered.
TOXICOLOGY HANDBOOK
Paediatric: initial paediatric dose is 0.02 mg/kg to a maximum of 0.5 mg.
HANDY TIPS
• Although the duration of action of physostigmine is relatively short
(about 2 hours), repeat doses are not always required after initial
reversal of delirium.
• Use of physostigmine may prevent the need to administer massive
doses of benzodiazepine to the delirious patient and thus reduce
the likelihood of excessive sedation and pulmonary aspiration.
• Consider physostigmine in the management of anticholinergic
delirium that persists in the recovering tricyclic antidepressant
overdose patient.
• Do not give physostigmine as an intravenous infusion – it is likely
to precipitate a cholinergic crisis.
• Neostigmine is not a substitute for physostigmine.
PITFALL
• Inadequate or excessive doses of physostigmine. This can usually
be avoided by careful titration of dose to clinical effect.
CONTROVERSIES
• Physostigmine fell out of favour in the treatment of anticholinergic
poisoning in the 1970s following a number of reports of
bradydysrhythmias and asystole. It is likely that the risk was
overestimated.
ERRNVPHGLFRVRUJ
• Relative value of benzodiazepines and physostigmine in the
management of anticholinergic delirium. Benzodiazepines are
useful in achieving sedation but will not reverse delirium.
• Physostigmine has been advocated in the management of
gamma-hydroxybutyrate (GHB) overdose, but its clinical utility in
this situation is unproven and unlikely to improve outcome
beyond that which is assured by good supportive care.
References
Burns MJ, Linden CH, Graudins A et al. A comparison of physostigmine and
benzodiazepines for the treatment of anticholinergic poisoning. Annals of Emergency
Medicine 2000; 35:374–381.
Suchard JR. Assessing physostigmine’s contraindication in cyclic antidepressant
ingestions. Journal of Emergency Medicine 2003; 25(2):185–191.
4.22 PRALIDOXIME
ANTIDOTES
This is the oxime available in Australasia to reactivate

acetylcholinesterase inhibition caused by organophosphates (OPs).
Presentation
Pralidoxime iodide 500 mg/20 mL vials
446 • Organophosphate poisoning
•
44
Carbamate poisoning
6
— Although not strictly indicated for carbamates, it should not

be withheld in severe poisoning or if there is any doubt
TOXICOLOGY HANDBOOK
regarding the nature of the agent.

• Nerve agent poisoning
CONTRAINDICATIONS
• Hypersensitivity
Mechanism of action
Pralidoxime reactivates acetylcholinesterase that has been inhibited by binding to OP or
carbamate pesticides. It is only effective if given before irreversible binding or ‘ageing’
takes place. Re-establishment of enzymatic function rapidly reverses the nicotinic and
muscarinic effects of OP poisoning. Atropine is usually administered prior to pralidoxime
and the effect at muscarinic receptors is synergistic. Atropine is not effective at nicotinic
receptors. An improvement in muscle strength may be observed within 10–40 minutes of
administration.
Pharmacokinetics
Following IV administration, pralidoxime has a volume of distribution of 0.8 L/kg. Over
80% of an administered dose is excreted unchanged by the kidney with an elimination
half-life of 75 minutes. These volumes of distribution and elimination half-lives increase in
poisoned patients and during continuous IV infusion. An infusion of 500 mg/hour
achieves levels of >4 microgram/mL (postulated target concentration) within 15 minutes
and maintains them for the duration of the infusion.
ADMINISTRATION
• The patient with confirmed organophosphate poisoning has a
life-threatening illness and is managed in a critical care
ERRNVPHGLFRVRUJ
environment with full monitoring and resuscitation facilities
available.
• Administer the initial dose of 2 g pralidoxime in 100 mL of normal
saline IV over 15 minutes
then
• Commence pralidoxime infusion at 500 mg/hour (pralidoxime 6 g
in 500 mL of normal saline at 42 mL/hour).
• Higher infusion rates are rarely indicated, but may be considered
if clinical response is poor.
• The infusion may be discontinued after 24 hours provided the
patient is clinically well; the time of cessation is within daylight
hours and the patient remains under close observation for a
further 24 hours. If clinical evidence of OP poisoning recurs, the
infusion is recommenced for a further 24 hours.
• When facilities are available to perform rapid red cell
anticholinesterase activity assays, these should be done before
the infusion is ceased and then repeated after 4–6 hours. If
activity is maintained, pralidoxime is no longer required.
ANTIDOTES
• Usually minimal or mild.
• Non-specific adverse effects include nausea, headache, dizziness,
drowsiness, blurred vision and hyperventilation.
• Rapid administration can cause tachycardia, laryngospasm,
muscle rigidity, hypertension and transient neuromuscular
447
blockade.
TOXICOLOGY HANDBOOK
Paediatric: children are treated with an initial dose of 25–50 mg/kg
followed by an infusion of 10–20 mg/kg/hour.
HANDY TIPS
• Administration beyond 24 hours after OP ingestion is
unlikely to be effective, but a therapeutic trial may still be
warranted.
• Poisoning from certain OPs may be less responsive to
pralidoxime than others.
PITFALLS
• Failure to administer an appropriate dose
• Inadequate duration of treatment
• Late initiation of treatment
CONTROVERSIES
• The value of pralidoxime in improving clinical outcome from OP
poisoning is disputed. Although pralidoxime has been shown to
reactivate red cell acetylcholinesterase in OP-poisoned patients, it
has not been shown to improve survival or reduce the need for
intubation. Some clinical trials associate poorer clinical outcome
with oxime therapy.
ERRNVPHGLFRVRUJ
• Optimal dosing and duration of pralidoxime is not established and
almost certainly varies with different OPs. It may be that currently
recommended doses are not optimal and this may contribute to
poor response to oximes observed in clinical trials.
• The role of pralidoxime in carbamate poisoning.
References
Buckley NA, Eddleston M, Li Y et al. Oximes for acute organophosphate poisoning.
Cochrane Database of Systematic Reviews 2011; 2.
Eddleston M, Eyer P, Worek F et al. Pralidoxime in acute organophosphorus insecticide
poisoning – a randomised controlled trial. PLoS Medicine 2009 June; 6(6):e1000104.
4.23 PYRIDOXINE
Vitamin B6
Intravenous pyridoxine is used in high doses to control the metabolic
acidosis and seizures associated with isoniazid overdose and poisoning
ANTIDOTES
from other hydrazine compounds.
Presentations
Pyridoxine hydrochloride 50 mg/mL vials
Pyridoxine hydrochloride 250 mg/mL vials, obtained under the Special Access Scheme
in Australia
448
44
• Metabolic acidosis and seizures induced by hydrazine

8
compounds (includes isoniazid, Gyromitra mushrooms and

TOXICOLOGY HANDBOOK
hydrazine, a component of jet and rocket fuels)

• Adjunct in the treatment of ethylene glycol toxicity
CONTRAINDICATIONS
Mechanism of action
The active form of pyridoxine, pyridoxal 5-phosphate (P5P), is known as vitamin B6. It is
an important cofactor in over 100 enzymatic reactions involving amino acid metabolism.
P5P is an essential coenzyme in the conversion of L-glutamic acid to GABA. The
hydrazines, including isoniazid, inhibit the formation of P5P, bind to and inactivate
existing P5P and enhance elimination of P5P, thereby producing a state of GABA
depletion leading to CNS excitation and seizures. Large doses of pyridoxine overcome
this inhibition and restore normal GABA concentration and activity.
Pharmacokinetics
Pyridoxine has an oral bioavailability of about 50% and a volume of distribution of 0.6 L/
kg. It is rapidly metabolised at extrahepatic sites to the active phosphate ester and other
compounds.
ADMINISTRATION
• EEG monitoring is mandatory during pyridoxine administration if
the patient is intubated and paralysed.
ERRNVPHGLFRVRUJ
• Isoniazid overdose
— Administer an initial dose of 1 g pyridoxine for each gram of
isoniazid ingested up to a maximum dose of 5 g (70 mg/kg in
children).
— Give this dose as a slow IV infusion at 0.5 g/minute until
seizures stop or infusion is complete. The remainder of the
dose may then be infused over 4 hours.
— If the ingested dose of isoniazid is unknown, give 5 g of
pyridoxine empirically.
— Benzodiazepines are given concomitantly, as they have a
synergistic effect in seizure management.
• Hydrazine or monomethylhydrazine poisoning
— Administer an initial bolus of 25 mg/kg intravenously.
• Ethylene glycol poisoning
— Give 50 mg IV every 6 hours.

• Control of seizures
ANTIDOTES
• Chronic high oral pyridoxine dosing is associated with peripheral
neuropathy, but this does not occur with acute dosing for
isoniazid overdose.
SPECIFIC CONSIDERATIONS 449

Pregnancy: no restriction on use
TOXICOLOGY HANDBOOK
HANDY TIPS
• Pyridoxine is readily available only in 50 mg vials. Large numbers
(100) of these will need to be procured to treat a single case of
isoniazid poisoning. If the recommended dose cannot be
immediately obtained, all available pyridoxine, together with
high-dose benzodiazepines, should be administered as an interim
measure.
• Always administer benzodiazepines in addition to pyridoxine
because of the likely synergistic effect on seizure control.
PITFALL
• Failure to administer benzodiazepines concurrently.
CONTROVERSIES
• Human experience with pyridoxine in isoniazid poisoning is
confined to case reports. It may be that severe isoniazid toxicity
can be successfully managed using supportive care and high-
dose benzodiazepine therapy alone.
• Utility of pyridoxine in ethylene glycol poisoning.
Reference
Lheureux P, Penaloza A, Gris M. Pyridoxine in clinical toxicology: a review. European
Journal of Emergency Medicine 2005; 12:78–85.
ERRNVPHGLFRVRUJ
4.24 SODIUM BICARBONATE
Hyperosmolar sodium bicarbonate solutions are widely used in clinical
toxicology, both as an antidote to drugs that impair fast sodium channel
function and as an alkalinising agent to manipulate drug distribution and
excretion.
Presentations
Sodium bicarbonate 50 mmol/50 mL single-use pre-filled syringe
Sodium bicarbonate 100 mmol/100 mL vial
• Cardiotoxicity secondary to fast sodium channel blockade
— Tricyclic antidepressants
— Bupropion
— Chloroquine/hydroxychloroquine
— Dextropropoxyphene
ANTIDOTES
— Propranolol
— Type 1a and 1c antidysrhythmics
— Flecainide, quinidine, quinine
• Prevention of redistribution of drug to the CNS
— Severe salicylate poisoning
• Immediate correction of profound life-threatening metabolic
acidosis
450 — Cyanide poisoning
45
— Isoniazid overdose
0
— Toxic alcohol poisoning (ethylene glycol, methanol and other

TOXICOLOGY HANDBOOK
toxic alcohols)
• Enhanced urinary drug elimination
— Salicylate intoxication (any symptomatic patient)
— Phenobarbitone intoxication
• Increased urinary solubility
— Methotrexate toxicity
— Drug-induced rhabdomyolysis
CONTRAINDICATIONS
• Acute pulmonary oedema
• Hypokalaemia
• Metabolic or respiratory alkalosis
• Poorly controlled congestive cardiac failure
• Renal failure
• Severe hypernatraemia
Mechanism of action
Administration of hypertonic sodium bicarbonate provides both a sodium and a
bicarbonate load. The bicarbonate load increases plasma bicarbonate concentration,
buffers excess hydrogen ion concentration and raises serum pH. Administration of a
sufficient bicarbonate load also results in urinary bicarbonate excretion and an alkaline
urine pH. These properties allow sodium bicarbonate to be used with benefit in a number
of situations in clinical toxicology.
ERRNVPHGLFRVRUJ
Elevation of serum pH
• Improved fast sodium channel function
— A number of drugs cause cardiotoxicity by impairing sodium flux
through the fast sodium channels of the cardiac conducting system
during depolarisation.
— Raising the serum pH improves fast sodium channel function and
mitigates this toxic effect. Any increase from baseline pH is beneficial
but the effect is maximal at pH 7.50–7.55.
— The sodium load provided by sodium bicarbonate administration has a
separate but additive positive effect on sodium channel function.
• Alteration of drug distribution
— Elevation of serum pH can reduce the proportion of drug in un-ionised
form, reduce its ability to cross cell membranes and hence reduce the
proportion of drug that distributes to tissue compartments (especially
the CNS).
• Immediate correction of severe life-threatening metabolic acidosis
— Profound metabolic acidosis has negative effects on cardiovascular
function and may be life-threatening at pH approaching 6.7,
irrespective of the underlying toxic cause.
Alkalinisation of urine
•
ANTIDOTES
‘Ion trapping’ and enhanced urinary elimination
— An alkaline urinary pH can result in some drugs being predominantly in
an ionised form and unable to be reabsorbed across the tubular
epithelium.
• Increased solubility
— An alkaline urinary pH promotes water solubility of some drugs and of
myoglobin, thus preventing tubular precipitation and secondary renal
injury in addition to promoting urinary excretion.
451
Pharmacokinetics
+
Sodium bicarbonate (NaHCO3) dissociates in water to provide sodium (Na ) and
bicarbonate (HCO3−) ions. Sodium is the principal cation in the extracellular fluid.
TOXICOLOGY HANDBOOK
Bicarbonate is a normal constituent of body fluids and plasma concentration is
regulated. Under normal conditions, very little bicarbonate is excreted in the urine.
Bicarbonate combines with hydrogen ions to form carbonic acid, which dissociates to
form H2O and CO2.
ADMINISTRATION
Cardiotoxicity secondary to fast sodium channel blockade
• Resuscitation from severe cardiotoxicity (cardiac arrest,
ventricular dysrhythmias and hypotension)
— Sodium bicarbonate administration occurs in concert with
advanced cardiac life support, including establishment of
an airway, hyperventilation and administration of IV fluid
boluses.
— Give repeated boluses of 2 mmol/kg IV until cardiovascular
stability is achieved.
— Following clinical stabilisation, further administration of
sodium bicarbonate is guided by repeated blood gas
estimations.
• Maintenance of serum alkalinisation in severe cardiotoxicity
— Should be considered following resuscitation in the presence
of ventricular dysrhythmias, hypotension or a markedly wide
QRS complex (>140 ms).
— Commence an infusion of 150 mmol sodium bicarbonate
diluted in 850 mL normal saline at 250 mL/hour.
ERRNVPHGLFRVRUJ
— Check ABGs hourly and maintain serum pH in range of
7.50–7.55.
— Cease infusion following resolution of cardiovascular toxicity
as determined by clinical and ECG criteria.
— Note: In practice it is far easier and safer, and of comparable
efficacy, to maintain serum alkalinisation with hyperventilation
in the intubated patient.
Prevention of redistribution of salicylate to CNS
• The pH must be maintained above 7.4 at all times.
• The salicylate-poisoned patient with severe metabolic acidosis is
critically ill and usually intubated, and serum pH may be
maintained >7.4 by hyperventilation.
• Give sodium bicarbonate 2 mmol/kg IV bolus in an unwell
unintubated patient with salicylate poisoning.
• Then intubate, hyperventilate and recheck ABGs.
• Serum alkalinisation is maintained until definitive care with
haemodialysis.
Urinary alkalinisation
• Correct hypokalaemia if present.
ANTIDOTES
• Give 1–2 mmol/kg sodium bicarbonate IV bolus.

• Commence infusion of 150 mmol sodium bicarbonate in 850 mL
5% dextrose at 250 mL/hour.
• 20 mmol of KCl may be added to infusion to maintain
normokalaemia.
452
• Monitor serum bicarbonate and potassium at least every
4 hours.
• Regularly dipstick urine and aim for urinary pH >7.5.
45
2
• Continue until clinical and laboratory evidence of toxicity is

resolving.
TOXICOLOGY HANDBOOK
Note: Sodium bicarbonate (NaHCO3) should not be administered

through an intravenous line running fluids containing calcium or
magnesium.

• Alkalosis (serum pH >7.6 is detrimental to cardiovascular
function)
• Hypernatraemia and hyperosmolarity
• Fluid overload and acute pulmonary oedema
• Hypokalaemia
• Local tissue inflammation secondary to extravasation
Lactation: no restriction on use.
Paediatric: doses are the same as for adults on mmol/kg basis.
Reduced fluid volumes should be used in children.
HANDY TIPS
• Rapid correction of acidosis by administration of sufficient doses
of sodium bicarbonate is an essential component of the
resuscitation of a patient with severe tricyclic antidepressant
poisoning.
ERRNVPHGLFRVRUJ
• The frail elderly patient or patient with underlying cardiac disease
may not tolerate the fluid and osmotic load associated with
sodium bicarbonate administration.
PITFALLS
• Insufficient doses of sodium bicarbonate when attempting
resuscitation of severe tricyclic antidepressant poisoning.
• Failure to correct hypokalaemia when attempting urinary
alkalinisation.
• Failure to recognise and rapidly treat acidaemia in the patient with
severe salicylate poisoning.
CONTROVERSIES
• Utility and indications for urinary alkalinisation in toxic
rhabdomyolysis
• Value and indications for prophylactic serum alkalinisation in
tricyclic antidepressant poisoning
• Relative efficacy of hyperventilation versus administration of
ANTIDOTES
sodium bicarbonate in the management of tricyclic antidepressant
toxicity
• Precise mechanism by which urinary alkalinisation enhances
salicylate elimination
References
Bradberry SM, Thanacoody HK, Watt BE et al. Management of the cardiovascular 453
complications of tricyclic antidepressant poisoning: role of sodium bicarbonate.
Proudfoot AT, Krenzelok EP, Brent J et al. Does urine alkalinization increase salicylate
TOXICOLOGY HANDBOOK
elimination? If so, why? Toxicological Reviews 2003; 22(3):129–136.
4.25 SODIUM CALCIUM EDETATE

Calcium disodium versenate, Calcium disodium edetate, Calcium
disodium ethylenediaminetetraacetic acid (EDTA)
An intravenous heavy metal chelating agent primarily used in the
treatment of severe lead poisoning, including lead encephalopathy.
Presentations
Sodium calcium edetate 1 g/5 mL ampoules
• Lead encephalopathy
• Severely symptomatic lead poisoning without encephalopathy
• Asymptomatic or mildly symptomatic lead poisoning (lead level
>70 microgram/dL or 3.38 micromol/L)
• Second-line chelating agent when succimer is either not available
or not tolerated by the patient
• Other heavy metal poisoning (efficacy unknown)
CONTRAINDICATIONS
• Relative contraindication: anuric renal failure
ERRNVPHGLFRVRUJ
Mechanism of action
EDTA binds to divalent and trivalent metals, the calcium component of EDTA is
displaced and a stable water-soluble chelate is formed, which is readily excreted in the
urine.
Pharmacokinetics
Absorption of EDTA is incomplete following oral administration and this antidote is only
administered by the intravenous route. The volume of distribution is small and
approximates that of the extracellular fluid compartment. It is not metabolised. Excretion
is urinary and largely dependent on the glomerular filtration rate. With normal renal
function, the elimination half-life is 20–60 minutes.
ADMINISTRATION
• Lead encephalopathy
— This patient is critically unwell and managed in intensive care.
— Commence dimercaprol (BAL) at 4 mg/kg IM every 4 hours
and continue for 5 days (see Chapter 4.7: Dimercaprol).
— Dilute EDTA 50–75 mg/kg in 500 mL of normal saline or 5%
dextrose and infuse over 24 hours starting 4 hours after first
ANTIDOTES
dose of dimercaprol.
• Symptomatic lead poisoning without encephalopathy
— This patient is unwell and managed in a high-dependency
environment.
— Commence dimercaprol (BAL) at 3 mg/kg IM every 4 hours
and continue for 5 days (see Chapter 4.7: Dimercaprol).
454 — Dilute EDTA 25–50 mg/kg in 500 mL of normal saline or 5%
dextrose and infuse over 24 hours starting 4 hours after first
45
4
dose of dimercaprol.
• EDTA therapy is usually continued for a maximum of 5 days.
TOXICOLOGY HANDBOOK
Therapy is then interrupted for 2 to 4 days to allow redistribution

of the lead prior to consideration of a further 5-day course.
• In the setting of encephalopathy, EDTA (and dimercaprol) should
be continued until the patient is clinically stable.
• Once clinically improved, chelation may be switched to oral
succimer if tolerated.

• Local pain and thrombophlebitis due to rapid IV administration.
Local phlebitis may be minimised by:
— Infusing dilute solution (<0.5%)
— Giving infusion over >4 hours.
• General systemic
— Malaise, fatigue, thirst, chills, fever, myalgias, dermatitis,
headache, anorexia, urinary frequency, sneezing, nasal
congestion, lacrimation, glycosuria, hypotension, transaminase
elevations and ECG changes
• Nephrotoxicity secondary to the dissociation of EDTA-metal
complexes in acid urine. The risk of nephrotoxicity during therapy
is reduced by:
— Ensuring adequate hydration and urine flow of 1–2 mL/kg/hour
— Limiting daily dose to 2 g (1 g in children)
— Continuous therapy for no longer than 5 days
— Daily monitoring of renal function.
ERRNVPHGLFRVRUJ
Paediatric: the doses of EDTA are the same for children, but may be
diluted in a smaller volume of fluid. Oral succimer is preferred as a
chelation agent whenever possible.
HANDY TIP
• The asymptomatic patient or minimally symptomatic patient, able
to tolerate oral therapy, should be treated with oral succimer
rather than EDTA.
PITFALL
• Inadvertent or mistaken administration of dicobalt edetate, an
antidote used in the treatment of cyanide poisoning.
CONTROVERSIES
ANTIDOTES
• EDTA may cause redistribution of lead from the soft tissues to the
CNS. For this reason EDTA is not given as sole therapy for lead
toxicity with levels >70 microgram/dL (3.38 micromol/L).
• Ability of EDTA chelation to reverse the neurobehavioural effects
of lead poisoning is unknown.
• Utility of diagnostic EDTA chelation lead mobilisation test to
evaluate total body lead burden.
455
References
Bradberry S, Vale A. A comparison of sodium calcium edetate (edetate calcium
TOXICOLOGY HANDBOOK
disodium) and succimer (DMSA) in the treatment of inorganic lead poisoning. Clinical
Toxicology 2009; 47:841–858.
Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics
1995; 96:155–160.
4.26 SODIUM THIOSULFATE

Sodium thiosulfate enhances the endogenous cyanide detoxification
capacity of the body. It is suitable to use alone in the treatment of mild
to moderately severe cases of cyanide poisoning, but should be used in
conjunction with other antidotes in severe cyanide toxicity.
Presentations
Sodium thiosulfate 12.5 g/50 mL vials
• Reasonable suspicion of cyanide poisoning
• May also be useful in poisoning from other agents including:
— Chlorate
— Cisplatin
— Bromate
— Bromine
— Iodine
ERRNVPHGLFRVRUJ
— Mustard gas
— Nitrogen mustard.
CONTRAINDICATIONS
• None: sodium thiosulfate has little toxicity at the recommended
doses
Mechanism of action
The major route for detoxification of cyanide is by conversion to thiocyanate. This
conversion is catalysed by the enzyme rhodanese. The capacity of rhodanese is limited
by the availability of suitable sulfur donors. Sodium thiosulfate acts as a sulfur donor for
rhodanese and greatly enhances the endogenous cyanide elimination capacity of the
body.
Pharmacokinetics
Thiosulfate is rapidly distributed throughout the extracellular space following intravenous
injection. Distribution into the brain is limited. Most is eliminated unchanged by renal
excretion, with an elimination half-life of 0.5–3 hours. A small amount is oxidised to
sulfate via a two-step hepatic process.
ANTIDOTES
ADMINISTRATION
• Administer 12.5 g sodium thiosulfate (50 mL of 25% solution) IV
over 10 minutes or 200 mg/kg IV over 10 minutes.
456
• Repeat after 30 minutes if clinical features of cyanide toxicity
persist.
45
6

TOXICOLOGY HANDBOOK


• Adverse effects are mild and of minor importance compared with
the risks associated with cyanide poisoning.
• Rapid injection may be associated with nausea and vomiting.
• Other minor adverse effects associated with thiocyanate
production are hypotension, nausea, headache, abdominal pain
and disorientation.
Paediatric: the recommended dose of 400 mg/kg is relatively higher
than for adults.
HANDY TIPS
• Collect blood for cyanide level before antidote administration.
• The combination of sodium thiosulfate, oxygen and supportive
therapy is probably sufficient to treat mild to moderately severe
cases of cyanide toxicity.
ERRNVPHGLFRVRUJ
• Sodium thiosulfate is valuable in doubtful cases of poisoning,
such as smoke inhalation, where it may have both therapeutic
and diagnostic value.
• In severe poisoning sodium thiosulfate should be given together
with other antidotes, with which it acts synergistically.
CONTROVERSY
• There are no clinical trials that assess the efficacy of thiosulfate in
humans. It has a relatively slow onset of action and should
probably be regarded as a second-line antidote for acute cyanide
poisoning.
References
Hall AH, Dart R, Bogdan G. Sodium thiosulfate or hydroxocobalamin for empiric
treatment of cyanide poisoning? Annals of Emergency Medicine 2007; 49:806–813.
ANTIDOTES
4.27 SUCCIMER
2,3-Dimercaptosuccinic acid (DMSA)
This orally active metal chelator is used to treat lead and other heavy
metal poisoning.
457
Presentations
Succimer 100 mg tablets (100), obtained under the Special Access Scheme in Australia
TOXICOLOGY HANDBOOK
• Adult lead poisoning
— Symptomatic
— Asymptomatic with blood lead level >60 microgram/dL (>2.9
micromol/L)
• Paediatric lead poisoning
— Symptomatic
— Asymptomatic with blood lead level >45 microgram/dL (2.17
micromol/L)
— Has been used to chelate mercury, arsenic, bismuth,
antimony and copper, but clinical experience is limited
CONTRAINDICATIONS
• Ongoing heavy metal exposure
Mechanism of action
Succimer is a water-soluble analogue of dimercaprol, which binds to heavy metal ions
via sulfhydryl groups. The succimer–metal complexes can then be excreted in the urine.
Pharmacokinetics
Following oral administration, succimer is rapidly absorbed and undergoes rapid
metabolism. Metabolites and some unchanged drug are excreted in the urine.
ERRNVPHGLFRVRUJ
ADMINISTRATION
• Lead poisoning
— May be administered on an outpatient basis.
— Give 10 mg/kg orally 3 times per day for 5 days.
then
— Give 10 mg/kg orally 2 times per day for 14 days.
— Blood lead levels are followed after completion of this initial
course.
— Further courses are indicated if blood levels rebound in the
absence of continued lead exposure.
— For more severe poisoning, succimer may be used after initial
chelation with parenteral agent (sodium calcium edetate) (see
Chapter 4.25: Sodium calcium edetate).
— In the absence of any guidelines, administration is the same
as for lead poisoning.
ANTIDOTES

• Hypersensitivity reactions
• Gastrointestinal upset is very common with this foul-smelling drug
— Symptomatic care for gastrointestinal symptoms.
— Converting to parenteral therapy may occasionally be
necessary.
• Transient liver function test abnormalities (occurs in up to 60% of
458 patients)
• Reversible neutropenia (rare)
45
8
TOXICOLOGY HANDBOOK
Pregnancy: safety is not established. Consideration is given to
chelation therapy at lower blood levels because of the susceptibility
of the fetal central nervous system to lead.
Paediatric: the doses for succimer are the same. It is generally
accepted that the blood lead level threshold for chelation is lower in
children than adults.
HANDY TIPS
• The asymptomatic patient or minimally symptomatic patient, able
to tolerate oral therapy, should be treated with oral succimer
rather than sodium calcium edetate.
• Succimer can be given on an outpatient basis to compliant
patients.
PITFALL
• It may be difficult to obtain succimer – it is only available in
Australia under the Special Access Scheme.
CONTROVERSY
• The threshold blood lead level for succimer chelation in children is
extremely controversial. Although relatively low blood lead levels
may have an adverse effect on neurodevelopment, the evidence
to date does not suggest that chelation therapy improves
outcome.
ERRNVPHGLFRVRUJ
References
Bradberry S, Vale A. Dimercaptosuccinic acid (succimer; DMSA) in inorganic lead
poisoning. Clinical Toxicology 2009; 47; 617–631.
Dietrich KN, Ware HH, Salganik M et al. Effect of chelation on the neuropsychological
and behavioral development of lead-exposed children after school entry. Pediatrics
2004; 114:19–26.
Treatment guidelines for lead exposure in children: Committee on Drugs. Pediatrics
1995; 96: 155–160.
4.28 VITAMIN K
Phytomenadione, Phytonadione, Vitamin K1
An essential cofactor in the synthesis of clotting factors II, VII, IX and X.
It is used for the reversal of coumadin-induced coagulopathy.
Presentations
Phytomenadione 2 mg/0.2 mL ampoules
ANTIDOTES
Phytomenadione 10 mg/1 mL ampoules
• Significant coumadin-induced coagulopathy:
— Therapeutic over-warfarinisation
— Intentional warfarin overdose
— Ingestion of long-acting anticoagulant rodenticides 459
(e.g. brodifacoum)
CONTRAINDICATIONS
TOXICOLOGY HANDBOOK
Mechanism of action
Phytomenadione is a synthetic fat-soluble analogue of naturally-occurring vitamin K1, an
essential cofactor in the synthesis of clotting factors II, VII, IX and X. The coumadin
anticoagulants inhibit vitamin K1 2,3-epoxide reductase, thus preventing the formation of
vitamin K hydroxyquinone, the active form of vitamin K. This leads to impaired formation
of clotting factors. Administration of high doses of vitamin K is able to overcome this
effect and restore normal levels of clotting factors.
Pharmacokinetics
Oral bioavailability is variable and dependent on bile salts, but is usually about 50%. It is
rapidly metabolised by the liver, with an elimination half-life of about 2 hours. The
increase in blood coagulation factors is delayed 6–12 hours after an oral dose and 3–6
hours after an IV dose.
ADMINISTRATION
The approach and dosing of Vitamin K varies according to the clinical
indication and relative need to maintain anticoagulation.
Therapeutic over-warfarinisation
• See Appendix 5: Therapeutic over-warfarinisation.
Warfarin overdose
• No therapeutic requirement for warfarin anticoagulation (patient
took someone else’s warfarin)
— Give vitamin K 5 mg PO or IV daily for 2 days.
— INR can be checked at 48 hours as an outpatient.
ERRNVPHGLFRVRUJ
• Therapeutic requirement for warfarin anticoagulation
— Closely monitor INR (at least every 6 hours).
— Give vitamin K 0.5–2 mg IV if INR >5.
— Continue close monitoring of INR.
— Give repeat doses of vitamin K 0.5–2 mg IV if INR remains at
or returns to >5.
— Start heparin if INR falls to <2 and absolute indication for
anticoagulation (e.g. mechanical heart valve).
Ingestion of long-acting anticoagulant rodenticide
• Very large daily doses of oral vitamin K are required for a period
of weeks to months if anticoagulation develops.
• Initial daily dose is variable and determined under close medical
supervision with repeated INR estimations.
• Close medical supervision is also necessary during treatment to
ensure compliance and safe withdrawal of vitamin K.
• Note: Active bleeding or high-risk of active bleeding (INR >9)
requires immediate reversal of anticoagulation by administration
of prothrombin complex concentrate and fresh frozen plasma,
ANTIDOTES
in addition to vitamin K administration to achieve sustained

reversal.

• Minor facial flushing, chest tightness, dyspnoea or dizziness with
IV administration
460 • Anaphylaxis following IV administration (rare)
• Warfarin resistance and over-correction of anticoagulation
46
— Manage with heparinisation until warfarin resistance has

0
resolved and therapy can be re-established.

TOXICOLOGY HANDBOOK
Paediatric: treat suspected paediatric ingestion of warfarin tablets
(>0.5 mg/kg) empirically with a single dose of vitamin K solution 5 mg
PO. This obviates the need for repeated blood tests.
HANDY TIPS
• Never give vitamin K by the intramuscular route.
• The injectable formulation of vitamin K is suitable for oral
administration.
• Single unintentional acute ingestion of an anticoagulant
rodenticide by a child does not involve a sufficient dose to cause
anticoagulation. Neither medical assessment nor vitamin K
therapy is necessary.
PITFALLS
• Administration of excessive doses of vitamin K in patients with an
absolute indication for anticoagulation. The resulting warfarin
resistance necessitates prolonged heparin administration prior to
successful reintroduction of warfarin therapy.
• Administration of vitamin K prior to demonstration of
anticoagulant effect in adults who self-poison with long-acting
anticoagulant rodenticides.
ERRNVPHGLFRVRUJ
CONTROVERSIES
• The threshold INR for vitamin K administration following
therapeutic over-warfarinisation or warfarin overdose.
• Duration of therapy in deliberate self-poisoning. Administration of
Vitamin K for 2–7 days has been advocated due to prolonged
warfarin half-life in overdose.
References
Baker RI, Coughlin PB, Gallus AS et al. Warfarin reversal: consensus guidelines, on
behalf of the Australasian Society of Thrombosis and Haemostasis. Medical Journal
of Australia 2004; 181(9):492–497.
Bruno GR, Howland MA, McMeeking A, Hoffman RS. Long-acting anticoagulant
overdose: brodifacoum kinetics and optimal vitamin K dosing. Annals of Emergency
Medicine 2000; 36(3):262–267.
Dentali F, Ageno W, Crowther M. Treatment of coumarin-associated coagulopathy: a
systematic review and proposed treatment algorithms. Journal of Thrombosis and
Haemostasis 2006; 4:1853–1863.
Isbister GK, Hackett LP, Whyte IM. Intentional warfarin overdose. Therapeutic Drug
Monitoring 2003; 25(6):715–722.
ANTIDOTES
461
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
CHAPTER 5
ENVENOMINGS
5.1 Black snake 464

5.2 Brown snake 468
5.3 Death adder 471
5.4 Tiger snake group 474
5.5 Taipan 478
5.6 Sea snake 481
5.7 Australian scorpions 483
5.8 Bluebottle jellyfish (Physalia species) 485
5.9 Stonefish 486
5.10 Box jellyfish 488
5.11 Irukandji syndrome 491
5.12 Blue-ringed octopus 494
5.13 Redback spider 496
5.14 Funnel-web (big black) spider 498
5.15 White-tailed spider 501
5.16 Ticks 502
ERRNVPHGLFRVRUJ
5.1 BLACK SNAKE Distribution of mulga snakes
• Pseudechis australis: mulga or king Perth Hills

brown snake Upper
• Pseudechis butleri: Butler’s or yellow- Swan Moree
bellied black snake
• Pseudechis colletti: Collett’s snake
• Pseudechis guttatus: blue-bellied or
spotted black snake
• Pseudechis papuanus: Papuan black
snake
• Pseudechis porphyriacus: red-bellied or
common black snake
Kalgoorlie
Mulga snakes are large aggressive Mildura
snakes found throughout inland and NOT Eyre
northern Australia. They usually inflict Peninsula Orange
a large, painful bite, produce a
significant amount of venom and are
ENVENOMINGS
potentially lethal. Envenoming by the

Collett’s snake is rare, has only been Distribution of red-bellied
black snakes
reported in snake handlers and has
features of envenoming similar to Big Tableland
mulga snakes. Red-bellied black to Mt Elliot Proserpine to
snakes are found along the south- Eungella
eastern coastal areas and the
envenoming is not usually lethal, even
464 without treatment.
46
4
Bourke
TOXINS
TOXICOLOGY HANDBOOK
Mulga snake venom contains

haemotoxins, myotoxins,
neurotoxins and anticoagulant
toxins. It has no procoagulant
toxins. Red-bellied and blue- Wilcannia
bellied black snake venoms have
Gladstone
less potent toxins.
CLINICAL PRESENTATION AND COURSE

Mulga snake, Collett’s snake, Butler’s snake and Papuan
black snake
• These snakes characteristically inflict a large, painful bite leading
to extensive local tissue swelling. Regional lymphadenitis may
develop.
• Systemic features of headache, abdominal pain, nausea, vomiting
or diarrhoea occur in almost all envenomed patients within a short
time of the bite. Generalised myalgia and muscle weakness
develop within 6 hours of envenoming and last several days in
untreated patients.
• Myotoxicity is frequent, peak CK concentrations occur within
24–72 hours of the bite and myoglobinuria may develop.
ERRNVPHGLFRVRUJ
• Anticoagulant coagulopathy is frequent but clinical features, such
as bleeding gums, are rare.
• Acute haemolysis may occur and result in anaemia, although
rarely of sufficient magnitude so as to require a blood
transfusion.
Red-bellied and blue-bellied black snakes
• Envenoming by the red-bellied or blue-bellied black snake is
usually associated with local pain along with systemic symptoms
including nausea, vomiting and abdominal pain.
• A small proportion of cases develop myotoxicity. This is usually
characterised by myalgias and a minor CK rise but is occasionally
more severe.
• Anticoagulant coagulopathy may occur but is not usually
associated with clinically significant bleeding.
• Minor, but unpleasant, long-term neurological sequelae, such as
anosmia and areas of numbness, paraesthesia or pain in the
region of the bite site, are reported.
MANAGEMENT
ENVENOMINGS
See Chapter 2.1: Approach to snakebite for a guide to the
principles of snakebite management.
Pre-hospital
• Apply a pressure bandage with immobilisation (PBI).
• Transport to a hospital capable of providing definitive care.
Hospital
Resuscitation and supportive care 465
• Black snake envenoming is rarely an immediate life-threatening
emergency. However, patients should still be managed in
an area capable of cardiorespiratory monitoring and
TOXICOLOGY HANDBOOK
resuscitation.
• Watch for evidence of myotoxicity.
Antivenom
• CSL monovalent Black Snake Antivenom (see Chapter 6.1) is
used to treat envenoming by mulga, Collett’s, Butler’s and
Papuan black snakes. Early administration (within 3 hours of the
bite) appears to prevent myotoxicity.
• Administration of one ampoule (18,000 units) of CSL monovalent
Black Snake Antivenom is indicated following early presentation
after a bite by one of the above snakes where there are systemic
symptoms of envenoming, laboratory evidence of anticoagulant
coagulopathy or laboratory evidence of myotoxicity (CK rise
above 1000 IU/L).
• CSL monovalent Tiger Snake Antivenom or CSL monovalent
Black Snake Antivenom (see Chapters 6.1 and 6.4) is used to
treat envenoming by red-bellied and blue-bellied black snakes.
The antivenoms are equally effective but Tiger Snake Antivenom
has the advantages of being more widely available, cheaper and
of lower volume.
• Administration of CSL monovalent Tiger Snake Antivenom or CSL
monovalent Black Snake Antivenom is indicated following early
ERRNVPHGLFRVRUJ
presentation after a bite by a red-bellied or blue-bellied black
snake where there are significant systemic symptoms or
laboratory evidence of anticoagulant coagulopathy. Early
administration (within 4 hours of the bite) may prevent
myotoxicity.
INVESTIGATIONS
• The diagnosis of envenoming is based on the correlation of
history, clinical features and laboratory data.
• Routine laboratory investigations following snakebite include:
FBC, EUC, CK and coagulation profile (INR, APTT, fibrinogen,
d-dimer) at presentation and at intervals thereafter (see Chapter
2.1: Approach to snakebite).
• CK is used as a marker of myotoxicity. However, it may not
become grossly abnormal (>1000 IU/L) for many hours. CK levels
are repeated every 6 hours if the patient is symptomatic. If the
patient is asymptomatic with mild elevation of CK or APTT,
recheck every 12 hours.
• The anticoagulant coagulopathy of black snake envenoming is
ENVENOMINGS
characterised by:
— Elevated APTT and INR (usually mild)
— Normal fibrinogen
— Normal d-dimer and fibrin degradation products
— Normal platelet count.
• The Snake Venom Detection Kit (SVDK) is not used to
diagnose envenoming. Instead, it is used to determine
the correct monovalent antivenom if one or more snake
466 types could be responsible for the observed clinical
features.
46
6
TOXICOLOGY HANDBOOK
• Elevation of the CK may also be observed in taipan and tiger

snake envenoming.
• In contrast to the venom-induced consumptive coagulopathy
(VICC) observed in brown, taipan and tiger snake envenoming,
the abnormalities of APTT and INR in black snake
envenoming are usually mild and the d-dimer and fibrinogen
level normal.
• Death adders may cause a painful bite. Presentation may include
early clinical features of a symmetrical descending flaccid
paralysis (e.g. ptosis or diplopia), but myotoxicity and coagulation
defects do not occur.

• All patients must be admitted for observation to a hospital
capable of providing definitive care (see Chapter 2.1: Approach
to snakebite).
• Patients who have no clinical features and no laboratory
evidence of myotoxicity at 12 hours are not envenomed
and may be discharged. Discharge should not occur at
night.
ERRNVPHGLFRVRUJ
• Envenomed patients may be discharged following antivenom
administration if they are clinically well, their coagulation studies
and CK are improving, and there is no evidence of clinically
significant renal failure.
HANDY TIPS
• The mulga snake is sometimes referred to as the king brown
snake; however, it is not a brown snake and Brown Snake
Antivenom should not be administered.
• Envenoming by the red-bellied black snake or blue-bellied black
snake is frequently mild and antivenom may not be indicated. If
antivenom is indicated, Tiger Snake Antivenom may be used as
an alternative to Black Snake Antivenom.
• Envenoming by an Australian snake, associated with local pain,
headache, nausea and vomiting, and a mild anticoagulant
coagulopathy (increased APTT but normal fibrinogen), is highly
suggestive of black snake envenoming.
PITFALLS
ENVENOMINGS
• Failure to recognise that snakebite may have occurred, institute
early PBI or to manage the patient in a hospital setting for an
appropriate duration.
• Inaccurate snake identification.
• Misinterpretation of a SVDK result.
• Administration of antivenom to a patient who is not
envenomed.
467
CONTROVERSIES
• The point at which slowly evolving myotoxicity is treated
with antivenom. Antivenom prevents progression of muscle
TOXICOLOGY HANDBOOK
injury, but does not reverse injury that has already occurred.
Many experienced clinicians treat with antivenom if CK
exceeds 1000 IU/L. However, early administration of
antivenom (within 5 hours of the bite) may prevent myotoxicity
altogether.
• The indications for antivenom administration following red-bellied
black snake envenoming and the antivenom of choice (Tiger or
Black Snake Antivenom).
References
Churchman A, O’Leary MA, Buckley NA et al. Clinical effects of red-bellied black snake
(Pseudechis porphyriacus) envenoming and correlation with venom concentrations:
Australian Snakebite Project (ASP-11). Medical Journal of Australia 2010;
193:696–700.
Currie BJ. Snakebite in tropical Australia: a prospective study in the ‘Top End’ of the
Northern Territory. Medical Journal of Australia 2004; 181:693–697.
Johnston CI, Brown SGA, O’Leary MA et al. Mulga snake (Pseudechis australis)
envenoming: a spectrum of myotoxicity, anticoagulant coagulopathy, haemolysis
and the role of early antivenom therapy – Australian Snakebite Project (ASP-19).
White J. A clinician’s guide to Australian venomous bites and stings: Incorporating the
ERRNVPHGLFRVRUJ
5.2 BROWN SNAKE Distribution of brown snakes
• Pseudonaja affinis: dugite

• Pseudonaja guttata: spotted brown
snake
• Pseudonaja inframacula: peninsula
brown snake
• Pseudonaja ingrami: Ingram’s brown
snake
• Pseudonaja mengdeni: western brown
snake or gwardar
• Pseudonaja modesta: ringed brown Rottnest
snake Island
• Pseudonaja nuchalis: tropical brown
snake
• Pseudonaja textilis: eastern brown snake
Brown snakes are the most common cause of severe envenoming and
death from snakebite in Australia. The most important manifestation of
ENVENOMINGS
envenoming is venom-induced consumptive coagulopathy (VICC).
TOXINS
The venom contains procoagulants, cardiotoxins and a potent
presynaptic neurotoxin (textilotoxin).

468 • Patients may present asymptomatic with no obvious bite site.
• Non-specific systemic features of envenoming include headache,
46
nausea, vomiting and abdominal pain.

8
• Envenoming may be heralded by pre-syncope or sudden collapse.

TOXICOLOGY HANDBOOK
• Early death occurs rarely, probably secondary to direct

cardiotoxicity.
• The hallmark of brown snake envenoming is VICC. This develops
soon after the bite and may manifest clinically as bleeding gums,
persistent haemorrhage at venesection sites or intracerebral
haemorrhage. Partial VICC occurs in about 20% of brown snake
envenomings.
• Thrombotic microangiopathy, characterised by thrombocytopenia,
microangiopathic haemolytic anaemia (MAHA) and acute renal
failure, occurs in about 10% of brown snake envenomings.
Oliguria may be present from the time of envenoming.
• Myotoxicity does not occur and significant neurotoxicity is rare,
despite the presence of a neurotoxin in the venom. Mild diplopia
and ptosis are observed occasionally.
MANAGEMENT
Pre-hospital
ERRNVPHGLFRVRUJ
Hospital
• Brown snake envenoming is a potentially life-threatening
emergency and patients should be managed in an area capable
of cardiorespiratory monitoring and resuscitation.
include:
— Hypotension
— VICC with uncontrolled haemorrhage.
• In cardiac arrest secondary to brown snake envenoming, undiluted
antivenom administered as a rapid IV push may be life saving.
Antivenom
• CSL Brown Snake Antivenom (see Chapter 6.2) is the specific
treatment of envenoming. A dose of one ampoule (1000 units) is
indicated for systemic envenoming, as evidenced by collapse or
objective clinical evidence of VICC or partial VICC.
INVESTIGATIONS
ENVENOMINGS
• Envenoming is diagnosed if there is a history of collapse,
objective clinical evidence of VICC or laboratory abnormalities
consistent with brown snake envenoming during 12 hours of
observation.
2.1: Approach to snakebite). 469
• ‘Complete’ VICC is defined as:
— Elevated INR (at least >3 but usually unrecordable)
TOXICOLOGY HANDBOOK
— Undetectable fibrinogen
— Elevated d-dimer (>100 × normal).
• ‘Partial VICC’ is defined as:
— INR abnormal but <3
— Low but detectable fibrinogen.
• Recovery from VICC (INR returning to <2) usually occurs between
10 and 20 hours after the bite.
• Thrombocytopenia may develop.
• Monitor for deteriorating renal function and evidence of MAHA,
indicated by raised lactate dehydrogenase (LDH) and fragmented
red blood cells on blood film.
• The Snake Venom Detection Kit (SVDK) is not used to diagnose
envenoming. Instead, it is used to determine the correct
monovalent antivenom if one or more snake types could be
responsible for the observed clinical features.
• Tiger snake and brown snake envenoming may be
indistinguishable, early in the course, as both feature VICC and
may present with early collapse. However, in tiger snake
envenoming, evidence of neurotoxicity and myotoxicity may
develop over the ensuing hours.
ERRNVPHGLFRVRUJ
• Taipan envenoming also features VICC, but it is usually
associated with early neurotoxicity and myotoxicity.
• Black snake envenoming is associated with a mild anticoagulant
coagulopathy, normal fibrinogen levels and myotoxicity.

to snakebite).
• Patients with no clinical features and no laboratory evidence of
coagulopathy at 12 hours after the bite are not envenomed and
may be discharged. Discharge should not occur at night.
• Envenomed patients should be monitored for a further 24 hours
following antivenom. This time frame allows laboratory
confirmation of recovery from VICC and determination of whether
they are developing thrombotic microangiopathy. The patient is fit
for discharge at the end of that time if they are clinically well, the
INR has returned to <2 and renal function and blood counts
remain stable.
• Patients who develop thrombotic microangiopathy require a more
ENVENOMINGS
prolonged admission for management of acute renal failure and

MAHA. Up to 8 weeks of dialysis may be required until renal
function recovers.
HANDY TIPS
• The majority of patients bitten by brown snakes do not become
envenomed.
470 • In the early stages, brown snake envenoming may be
indistinguishable from tiger snake envenoming.
47
•
0
Early collapse after a brown snakebite is strongly suggestive of

envenoming.
TOXICOLOGY HANDBOOK
• Point-of-care INR and d-dimer testing should never be used in

suspected snakebite cases – very high false positive and false
negatives rates are documented.
PITFALLS
CONTROVERSIES
• Recent evidence suggests that administration of antivenom does
not hasten recovery from VICC. It may, however, reverse or
prevent other manifestations of envenoming.
• Administration of clotting factors (fresh frozen plasma or
cryoprecipitate) after antivenom administration is associated with
earlier recovery from VICC but not with earlier discharge from
hospital.
• The efficacy, safety and indications for clotting factor replacement
after venom neutralisation in VICC are not yet well defined.
ERRNVPHGLFRVRUJ
• Plasmapheresis has been used to treat thrombotic
microangiopathy, but its role remains undefined.
References
Allen GE, Brown SCA, Buckley NA et al. Clinical effects and antivenom dosing in brown
snake (Pseudonaja spp.) envenoming – Australian Snakebite Project (ASP-14). PLoS
ONE 2012; 7(12):e53188.
Brown SG, Caruso N, Borland M et al. Clotting factor replacement and recovery from
snake venom-induced consumptive coagulopathy. Intensive Care Medicine 2009;
35(9):1532–1538.
Isbister GK, Buckley NA, Page CB et al. A randomized controlled trial of fresh frozen
plasma for treating venom-induced consumption coagulopathy in cases of Australian
snakebite (ASP-18). Journal of Thrombosis and Haemostasis 2013; 11:1310–1318.
Isbister GK, Duffull SB, Brown SGA. Failure of antivenom to improve recovery in
Australian snakebite coagulopathy. Quarterly Journal of Medicine 2009;
102(8):563–568.
Isbister GK, Little M, Cull G et al. Thrombotic microangiopathy from Australian brown
snake (Pseudonaja) envenoming. Internal Medicine Journal 2007; 37(8):523–528.
Sutherland SK, Tibballs J. Australian animal toxins: the creatures, their toxins and care of
the poisoned patient. South Melbourne: Oxford University Press; 2001.
ENVENOMINGS
5.3 DEATH ADDER Distribution of death adders
• Acanthophis antarcticus: common

death adder
• Acanthophis hawkei: Barkly Tableland
death adder 471
• Acanthophis laevis: smooth-scaled
death adder (PNG)
• Acanthophis praelongus: northern
TOXICOLOGY HANDBOOK
death adder
• Acanthophis pyrrhus: desert death
adder Mundaring
• Acanthophis rugosus: rough-scaled
Esperance
death adder (PNG)
• Acanthophis wellsi: Pilbara death NOT Victoria or
Tasmania
adder
Death adders are found throughout most
of mainland Australia and Papua New Guinea, but both bites and
envenoming are uncommon.
TOXIN
The venom contains a number of pre-synaptic and post-synaptic
neurotoxins. Other identified components include myotoxins,
pro-coagulants and anticoagulants.

• Pain or stinging at the bite site is common; however, puncture
wounds may not be apparent. Local swelling and bruising may
develop.
ERRNVPHGLFRVRUJ
• Systemic envenoming is characterised by a progressive
symmetrical descending flaccid paralysis, which usually manifests
within 6 hours. Early signs include ptosis, blurred vision, diplopia
and difficulty swallowing. In more severe cases there is
progression to generalised paralysis, respiratory failure and
secondary hypoxic cardiac arrest. With the institution of
advanced airway support, paralysis usually resolves
spontaneously after 1–2 days.
• Non-specific symptoms, principally nausea and vomiting, are
common.
• Myotoxicity is uncommon and not severe.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a general guide to the
Pre-hospital
ENVENOMINGS
Hospital
• Death adder envenoming is a potentially life-threatening
emergency and patients are managed in an area capable of
include:
— Descending flaccid paralysis with respiratory failure
472 — Hypotension.
• If respiratory failure is present and antivenom is not immediately
47
available, provision of an airway and mechanical ventilation are

2
life saving.
TOXICOLOGY HANDBOOK
Antivenom
• CSL monovalent Death Adder Antivenom (see Chapter 6.3) is the
specific treatment of envenoming. Systemic envenoming, with
objective evidence of paralysis, is treated with a dose of 1
ampoule (6000 units).
INVESTIGATIONS
2.1: Approach to snakebite). These investigations are usually
normal in death adder envenoming.
• Spirometry or peak flow measurements provide a surrogate
method of monitoring respiratory muscle strength and respiratory
function.
ERRNVPHGLFRVRUJ
• Envenoming by tiger, taipan and (rarely) brown snakes is
associated with neurotoxic paralysis. However, envenoming by
these snakes is usually associated with venom-induced
consumptive coagulopathy (VICC).

to snakebite).
• Patients who are not envenomed will have no clinical features of
paralysis at 12 hours after the bite and may be discharged.
• Envenomed patients may be discharged if they have complete
reversal of paralysis and remain clinically well for 24 hours
following antivenom administration.
HANDY TIPS
• Death adders are quiet and nocturnal. A common scenario is that
ENVENOMINGS
the victim is bitten on the ankle after treading on the snake while
walking outside with bare feet at dusk. The victim may feel little
more than a sting and not see the snake.
• A painful bite site associated with a symmetrical descending
flaccid paralysis, but normal blood tests, is characteristic of death
adder envenoming.
• Basic resuscitation with maintenance of airway and breathing is
life saving. 473
• In the absence of monovalent Death Adder Antivenom, 1 ampoule
of CSL Polyvalent Antivenom (contains 6000 units of Death Adder
Antivenom) may be administered as an alternative.
TOXICOLOGY HANDBOOK
• Death adder bite may be complicated by cellulitis at the bite site.
PITFALLS
• Administration of antivenom to a non-envenomed patient.
• Failure to detect early neurotoxicity: ptosis, double vision and
falling FEV1.
CONTROVERSIES
• The efficacy of antivenom in reversing or preventing neurotoxicity
is currently being questioned.
• The role of neostigmine as an alternative or adjunct to antivenom
treatment.
References
Currie BJ. Snakebite in tropical Australia: a prospective study in the ‘Top End’ of the
Northern Territory. Medical Journal of Australia 2004; 181:693–697.
ERRNVPHGLFRVRUJ
Johnston CI, O’Leary MA, Brown SCA et al. Death adder envenoming causes
neurotoxicity not reversed by antivenom – Australian Snakebite Project (ASP-16).
PLoS Neglected Tropical Diseases 2012; 6(9):e1841.
Lalloo DG, Trevett AJ, Black J et al. Neurotoxicity, anticoagulant activity and evidence of
rhabdomyolysis in patients bitten by death adders (Acanthophis sp.) in southern
Papua New Guinea. Quarterly Journal of Medicine 1996; 89:25–35.
Little M, Pereira P. Successful treatment of presumed death adder neurotoxicity using
anticholinesterases. Emergency Medicine 2000; 12:241–245.
5.4 TIGER SNAKE GROUP Distribution of tiger snakes
• Austrelaps labialis: pygmy copperhead Maryborough Sound

• Austrelaps superbus: common Fraser Island
Cooktown
copperhead
• Hoplocephalus bitorquatus: Moore
River
pale-headed snake
• Hoplocephalus bungaroides:
Point
Bunya
Mountains
broad-headed snake
Malcolm
• Hoplocephalus stephensii: Stephen’s
ENVENOMINGS
banded snake Orange

• Notechis scutatus (ater) occidentalis:
western or black tiger snake Garden Eyre
• Notechis scutatus: common or eastern and Peninsula
Carnac
tiger snake
Islands
• Tropidechis carinatus: rough-scaled NOT Kangaroo Bass
Strait
snake Rottnest Island
Island Islands
474 Tiger snakes are widespread throughout
southern Australia and are the second
47
most common cause of snakebite death in Australia. They coexist with

4
brown snakes in most areas and early clinical features of envenoming

TOXICOLOGY HANDBOOK
are very similar. Tiger snakes are the only venomous snakes in Tasmania
and a number of other islands.
TOXINS
Tiger snake venom contains pre- and post-synaptic neurotoxins,
procoagulants and myotoxins. Envenoming is classically associated
with a venom-induced consumptive coagulopathy (VICC), myotoxicity
and delayed onset neurotoxicity.

• Not all patients who are bitten become envenomed, but
serious envenoming may develop in patients without an
obvious bite site.
• Local pain occurs in most cases of envenoming and associated
minor bruising or swelling may be evident.
• Non-specific systemic features of envenoming occur in a majority
of patients and include headache, nausea, vomiting and
abdominal pain. These symptoms are usually present on
presentation to hospital.
• Systemic envenoming may be heralded by collapse and, rarely,
early death secondary to cardiac arrest.
ERRNVPHGLFRVRUJ
• VICC occurs rapidly and in almost all cases of envenoming by
snakes from the tiger snake group. VICC may be complete or
partial (see Investigations below). Complete VICC may manifest
clinically as bleeding gums, persistent haemorrhage at
venesection sites or intracerebral haemorrhage. VICC resolves
spontaneously within 10–20 hours of the bite.
• Neurotoxicity develops in about 30% of envenomings and is
usually apparent within 1–2 hours of the bite, but is slow in onset
and progresses over many hours. The earliest clinical features of
neurotoxicity are diplopia, blurred vision and ptosis. Rare cases
progress to respiratory and limb weakness requiring intubation
and ventilation.
• Myotoxicity develops in up to 20% of envenomings and may be
massive. It is manifest by myalgia and myoglobinuria but rarely
progresses to renal failure.
• Thrombotic microangiopathy, characterised by thrombocytopenia,
failure, is reported but less commonly than with brown snake
envenoming.
• Envenoming by the rough-scaled snake is similar to that of tiger
ENVENOMINGS
snakes.
• Copperhead snakes have neurotoxins and myotoxins, but
envenoming is usually mild and coagulopathy uncommon.
• Hoplocephalus species produce VICC, but not significant
paralysis or myotoxicity.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a guide to the 475
Pre-hospital
TOXICOLOGY HANDBOOK
Hospital
• Tiger snake envenoming is a potentially life-threatening
include:
— VICC with uncontrolled haemorrhage
— Paralysis with respiratory failure
— Hypotension.
• In cardiac arrest secondary to tiger snake envenoming, undiluted
antivenom administered as a rapid IV push may be life saving.
Antivenom
• CSL Tiger Snake Antivenom (see Chapter 6.4) is the specific
treatment of envenoming. Systemic envenoming, as evidenced by
collapse or objective evidence of coagulopathy, is treated with a
dose of 1 ampoule (3000 units).
• Note: Tiger Snake Antivenom does not reverse established
paralysis but does halt progression.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
• The diagnosis of tiger snake envenoming is based on the
correlation of history, geographical location, clinical features and
laboratory data.
• Envenoming is diagnosed if there is a history of collapse,
objective clinical evidence of coagulopathy or laboratory
abnormalities consistent with tiger snake envenoming during 12
hours of observation.
• ‘Partial’ VICC is defined as:
ENVENOMINGS

476 • Tiger snake and brown snake envenoming may be
47
indistinguishable, early in the course, as both feature VICC.

6
Significant paralysis or myotoxicity is rare in brown snake

envenoming.
TOXICOLOGY HANDBOOK
• Taipan envenoming also features VICC, but the onset of

neurotoxicity and myotoxicity is usually more rapid.
• Black snake envenoming is associated with myotoxicity, but only
a mild anticoagulant coagulopathy with normal fibrinogen levels.
• Death adder envenoming is associated with a symmetrical
descending flaccid paralysis, which is gradual in onset. It is
not usually associated with coagulopathy, myotoxicity or renal
failure.

to snakebite).
• Patients who are not envenomed will not have clinical features
of paralysis or laboratory evidence of coagulopathy at 12 hours
after the bite and may be discharged. Discharge should not occur
at night.
administration if they are clinically well, their coagulation studies
are improving (INR <2) and there is no evidence of clinically
significant renal failure.
ERRNVPHGLFRVRUJ
HANDY TIPS
• Tiger snake envenoming should be considered in the differential
diagnosis of collapse, paralysis or defibrinating coagulopathy.
• In the early stages, tiger snake envenoming may be
indistinguishable from brown snake envenoming.
negative rates are documented.
PITFALLS
• Administering antivenom to a patient who is not envenomed.
CONTROVERSIES
ENVENOMINGS
• Hoplocephalus spp. have traditionally been considered with the
tiger snake group based on phylogenetics and results of SVDK
testing. The clinical picture of envenoming is, however, closer to
that of brown snake and Hoplocephalus spp. envenoming should
perhaps be treated as a unique envenoming syndrome.
• Administration of clotting factors (fresh frozen plasma or 477
hospital. The efficacy, safety and indications for clotting factor
TOXICOLOGY HANDBOOK
replacement after venom neutralisation in VICC are not yet well
defined.
References
Brown SG, Caruso N, Borland M et al. Clotting factor replacement and recovery from
35(9):1532–1538.
Gan M, O’Leary MA, Brown SG et al. Envenoming by the rough-scaled snake
(Tropidectis carinatus): a series of confirmed cases. Medical Journal of Australia
2009; 191(3):183–186.
Australian snakebite coagulopathy. Quarterly Journal of Medicine 2009; 102(8):
563–568.
Isbister GK, O’Leary MA, Eliott M, Brown SGA. Tiger snake (Notechis spp) envenoming:
197(3):173-177.
Isbister GK, White J, Currie BJ et al. Clinical effects and treatment of envenoming by
Hoplocephalus spp. snakes in Australia: Australian Snakebite Project (ASP-12).
Toxicon 2011; 58:634–640.
Scop J, Little M, Jelinek GA et al. 16 years of severe tiger snake (Notechis) envenoming
in Perth, Western Australia. Anaesthesia and Intensive Care 2009; 37:613–618.
ERRNVPHGLFRVRUJ
5.5 TAIPAN Distribution of taipans

Coastal taipan
• Oxyuranus microlepidotus: inland (Oxyuranus scutellatus)
taipan, small-scaled or fierce snake Mitchell
• Oxyuranus scutellatus canni: Papuan Plateau
taipan Koolan
• Oxyuranus scutellatus: coastal taipan Island
• Oxyuranus temporalis: central ranges Birdum
taipan Normanton
Taipan envenoming is rare and

frequently lethal without antivenom
treatment. It is characterised by rapid (Oxyuranus
onset of venom-induced consumptive temporalis)
coagulopathy (VICC), neurotoxicity and Coober
myotoxicity. The Papuan taipan is the Pedy
Maclean
ENVENOMINGS
most medically important snake in Inland taipan

(Oxyuranus microlepidotus)
Papua New Guinea.
TOXINS
Taipan venom contains potent pre- and postsynaptic neurotoxins,
myotoxins and procoagulants (activators of the clotting pathway).
478 CLINICAL PRESENTATION AND COURSE

•
47
Bite sites have minimal or no symptoms, puncture marks are

8
often not apparent, and patients may not recognise that they have
been bitten.
TOXICOLOGY HANDBOOK
• Non-specific systemic features of envenoming include headache,

nausea and vomiting.
• Systemic envenoming may be heralded by collapse within a
few minutes of the bite and paralysis is usually apparent within
1–2 hours.
— Early signs of paralysis include ptosis, blurred vision, diplopia
and difficulty swallowing.
• Clinical features of VICC include bleeding gums, persistent
haemorrhage at venesection sites or intracerebral haemorrhage.
• Myotoxicity manifests by myalgia and myoglobinuria, and may
progress to cause renal failure.
• Thrombotic microangiopathy characterised by thrombocytopenia,
failure is a rare complication.
• Not all features of systemic toxicity (paralysis, coagulopathy and
myotoxicity) are necessarily present in every envenomed
individual.
MANAGEMENT
See Chapter 2.1: Approach to snakebite for a general guide to the
ERRNVPHGLFRVRUJ
Pre-hospital
Hospital
• Taipan envenoming is a time-critical and life-threatening
include:
— Hypotension
— Rapid onset paralysis with secondary respiratory failure
— VICC with uncontrolled haemorrhage
— Seizures.
• In cardiac arrest, undiluted antivenom administered as a rapid IV
push may be life saving.
Antivenom
• CSL Taipan Antivenom (see Chapter 6.5) is the specific treatment
ENVENOMINGS
of envenoming by taipans. Systemic envenoming, as evidenced
by collapse or objective evidence of paralysis or coagulopathy, is
treated with a dose of 1 ampoule (12 000 units).
• Note: If monovalent Taipan Antivenom is not immediately
available, each ampoule of CSL Polyvalent Antivenom contains
12 000 units of Taipan Antivenom and may be administered as a
substitute.
• Note: Taipan Antivenom does not reverse established paralysis,
but may halt the progression. 479
INVESTIGATIONS
•
TOXICOLOGY HANDBOOK
The diagnosis of envenoming is based on the correlation of
• ‘Partial’ VICC is defined as:
• Watch for deteriorating renal function and evidence of MAHA,
indicated by raised lactate dehydrogenase (LDH) and fragmented
red blood cells on blood film.
envenoming. It is used to determine the correct monovalent
antivenom if one or more snake types could be responsible for
the observed clinical features.
ERRNVPHGLFRVRUJ
• Brown snakes are found in the same geographic areas as taipans.
Brown snake envenoming may also cause VICC, but significant
paralysis and myotoxicity are rare.
• Snakes from the tiger snake group coexist with taipans in some
areas of Queensland. The clinical features of envenoming by
this group are similar to taipan envenoming, but the onset of
neurotoxicity and myotoxicity is more gradual (over several hours).
• Black snake envenoming is associated with myotoxicity and a
mild anticoagulant coagulopathy with normal fibrinogen levels.
• Death adder envenoming is associated with a symmetrical
descending flaccid paralysis, but is not associated with
coagulopathy, myotoxicity or renal failure.

to snakebite).
• Patients without clinical features of paralysis or laboratory evidence
ENVENOMINGS
of coagulopathy or myotoxicity at 12 hours are not envenomed and

may be discharged. Discharge should not occur at night.
• Envenomed patients can be discharged following antivenom
administration if they are clinically well, neurological findings are
mild and stable, their coagulation studies are improving (INR <2)
and CK is falling, and there is no evidence of significant renal
failure.
480
HANDY TIPS
48
• Taipan envenoming should be considered in the differential

0
diagnosis of patients in tropical Australia who present with

TOXICOLOGY HANDBOOK
collapse, paralysis or a defibrinating coagulopathy.

• VICC occurs in taipan, brown and tiger snake envenoming.
negative rates are documented.
PITFALLS
CONTROVERSIES
ERRNVPHGLFRVRUJ
defined.
References
Trevett AJ, Lalloo DG, Nwokolo NC et al. The efficacy of antivenom in the treatment of
bites by the Papuan taipan (Oxyuranus scutellatus canni). Transactions of the Royal
Society of Tropical Medicine and Hygiene 1995; 89:322–325.
Williams D, Bal B. Papuan Taipan (Oxyuranus scutellatus canni) envenomation in rural
Papua New Guinea. Annals of Australasian College of Tropical Medicine 2003;
4(1):6–9.
5.6 SEA SNAKE Distribution of sea snakes
ENVENOMINGS
At least 30 species of sea snakes are
Sydney
found around the coast of northern
Australia. They belong to the family
Hydrophiidae, and are closely related
to the venomous Australian terrestrial
snakes (Elapidae). They are inquisitive
but not aggressive and bites are rare.
Bites are most likely to occur when they
are handled, for example when they are 481
manually removed from fishing nets.
Esperance
TOXINS
TOXICOLOGY HANDBOOK
Sea snake venom is poorly
characterised but contains
neurotoxins and myotoxins.

• Most bites are very small, superficial, relatively painless and not
associated with local swelling or lymphadenitis.
• Non-specific features of envenoming include headache, nausea
and vomiting.
• Systemic envenoming is usually characterised by symmetrical
descending flaccid paralysis, which usually manifests within 6
hours. Early signs include ptosis, blurred vision, diplopia and
difficulty swallowing. If left untreated, it may progress to
generalised paralysis, respiratory failure and secondary hypoxic
cardiac arrest.
• Myotoxicity manifests as diffuse myalgias and myoglobinuria and
may progress to cause renal failure.
MANAGEMENT
ERRNVPHGLFRVRUJ
Pre-hospital
Hospital
• Sea snake envenoming is a time-critical life-threatening
include:
— Rapid onset paralysis with secondary respiratory failure
— Hypotension.
• If respiratory failure occurs and antivenom is not immediately
available, provision of an airway and mechanical ventilation is life
saving.
Antivenom
• CSL Sea Snake Antivenom (see Chapter 6.6) is the specific
treatment of envenoming. Systemic envenoming, as evidenced by
ENVENOMINGS
objective evidence of paralysis or myotoxicity, is treated with an

initial dose of 1 ampoule (1000 units).
INVESTIGATIONS
482 d-dimer) at presentation and at intervals thereafter (see Chapter
48

2
• CK is usually abnormal at the time of presentation if envenoming

has occurred. However, it may not become grossly abnormal
TOXICOLOGY HANDBOOK
(>1000 IU/L) for many hours. CK levels are repeated every

6 hours if the patient is symptomatic. If the patient is
asymptomatic with mild elevation of CK or APTT, recheck every
12 hours.
• The Snake Venom Detection Kit (SVDK) does not detect sea
snake venom.
• Other marine envenomings.
• Tiger snake and taipan envenoming also cause paralysis and
myotoxicity that evolve over a similar time course. However, they
are also associated with VICC, which does not occur in sea snake
envenoming.
• Black snake envenoming by the mulga snake is associated
with myotoxicity and, rarely, mild clinical features of
neurotoxicity. A mild anticoagulant coagulopathy with normal
fibrinogen is also commonly seen, which is absent in sea snake
envenoming.
• Death adder envenoming is associated with a postsynaptic
reversible symmetrical descending flaccid paralysis. However,
myotoxicity does not occur.
ERRNVPHGLFRVRUJ
to snakebite).
• Patients who do not display clinical features of paralysis or
laboratory evidence of myolysis at 12 hours after the bite are not
envenomed and may be discharged. Discharge should not occur
at night.
administration if they are clinically well, their CK levels are
improving and there is no evidence of clinically significant renal
failure.
HANDY TIP
• Snakebite at sea, on the beach or in estuarine waters may be
from a terrestrial snake.
PITFALLS
ENVENOMINGS
early PBI or manage the patient in a hospital setting for an
• Misinterpretation of a SVDK result. The CSL Snake Venom
Detection Kit does not detect sea snake venom.
CONTROVERSIES
• Larger doses of Sea Snake Antivenom (up to 4 ampoules) have 483
been recommended for ‘severe’ envenoming but it is unknown
whether such doses improve clinical response.
• If CSL Sea Snake Antivenom (SSAV) is unavailable, it is unclear
TOXICOLOGY HANDBOOK
whether any other CSL snake antivenom might be substituted. In
the past CSL Tiger Snake Antivenom (TSAV) was recommended
as a substitute with 3 ampoules of TSAV deemed equivalent to 1
ampoule of SSAV. Due to the nature of antivenom manufacturing
processes, it is not certain that the results of earlier research can
be extrapolated to the current TSAV product. The same concerns
apply to the use of CSL Polyvalent Antivenom as a substitute for
SSAV.
Reference
5.7 AUSTRALIAN SCORPIONS

• Bothriuridae
• Buthidae
• Urodacidae
Little is known about scorpion stings in Australia, but evidence suggests
that symptoms are usually limited to temporary pain at the sting site and
ERRNVPHGLFRVRUJ
occasional, minor, non-specific systemic symptoms. This is in contrast
to some scorpion stings elsewhere in the world, which are associated
with life-threatening envenoming.
TOXINS
Venom contains excitatory neurotoxins.

• Symptoms are usually confined to the site of the sting,
• Severe local pain is common and usually lasts 6–12 hours, but
may persist for up to 24 hours. Additional local symptoms
include erythema, tenderness, mild swelling, numbness and
paraesthesia.
• Systemic effects occur in a small minority of patients (10%). They
are mild, non-specific and self-limiting and include nausea,
headache and malaise.
MANAGEMENT
Pre-hospital
ENVENOMINGS
• Reassure the patient, apply an ice pack and give simple oral
analgesia such as paracetamol.
• Do not apply a pressure bandage with immobilisation (PBI).
• Patients do not require referral to hospital unless local symptoms
are refractory to simple analgesia or the diagnosis is in doubt.
Hospital
484 • Scorpion stings are not life threatening and resuscitation is not
48
required.
4
• Pain refractory to simple first aid and oral analgesia requires IV

opioid analgesia (e.g. morphine 0.1 mg/kg up to 5 mg, repeated
TOXICOLOGY HANDBOOK
every 10 minutes until appropriate analgesia is achieved).

Antivenom
• None available.
INVESTIGATIONS
• There are no confirmatory laboratory studies.
• Redback spider envenoming is characteristically associated with
local pain, sweating and piloerection. Systemic features include
pain at proximal sites, generalised sweating and dysphoria.
• Funnel-web spider envenoming is potentially lethal. It is
associated with a painful bite, sweating, agitation, piloerection,
cardiovascular abnormalities and neurological changes.
• Non-specific spider bites are associated with bite site pain and
mild systemic symptoms, such as nausea, headache, malaise or
vomiting. Significant cardiovascular, autonomic or neurological
features do not occur.
• Hymenoptera (bees, wasps, ants) also cause a painful sting.
• Centipedes cause a painful bite.
ERRNVPHGLFRVRUJ
• Patients do not require hospital assessment unless pain is
not controlled with simple analgesia or systemic symptoms
develop.
HANDY TIP
• The smallest scorpions cause the most painful stings.
Reference
Isbister GK, Volschenk ES, Balit CR et al. Australian scorpion stings: a prospective study
of definitive stings. Toxicon 2003; 41:877–883.
5.8 BLUEBOTTLE JELLYFISH (PHYSALIA SPECIES)

The bluebottle ‘jellyfish’ is responsible for thousands of stings on
Australian beaches each year. It is not actually a single organism but is
made up of a number of zooids. Each zooid has a specific function and
ENVENOMINGS
together they function as a single animal. Clinical features include
intense local pain and dermal erythema. Hot water immersion provides
safe symptomatic relief. Unlike Physalia stings in other parts of the
world, major systemic envenoming does not occur.
TOXINS
The toxins are contained within nematocysts on the tentacles and
released on contact. A complex mixture of glycoproteins, they are yet
to be well characterised. 485

•
TOXICOLOGY HANDBOOK
Stings are associated with immediate burning pain, typically
lasting up to 2 hours, and linear or elliptical erythematous welts.
• Non-specific systemic symptoms, such as nausea, headache or
malaise, may occur.
MANAGEMENT
• Stings are mild, self-limiting and respond to first aid measures.
• Reassure the patient.
• Place under a hot shower for 20 minutes (ideal temperature
45°C). The shower should be hot but not scalding or
uncomfortable.
• Administer simple oral analgesics such as paracetamol.
• Do not apply a pressure bandage with immobilisation (PBI) or
vinegar, as this may worsen local symptoms.
• Transport to hospital is not usually required.
Antivenom
• None available.
INVESTIGATIONS
• The diagnosis is clinical, based on a high index of suspicion and
correlation of history and characteristic features.
ERRNVPHGLFRVRUJ
• Pain associated with irukandji syndrome is usually delayed,
severe and generalised. Significant linear dermal markings or
welts are not seen.
• Envenoming by the box jellyfish (Chironex fleckeri) is associated
with immediate pain and obvious dermal markings (large welts).
Tentacles may be seen adhering to the skin.

• Most patients do not require any care beyond first aid.
HANDY TIP
• Ice packs were previously recommended as first aid for stings. The
superiority of hot water has now been conclusively demonstrated.
References
Loten C, Stokes B, Worsley D et al. A randomised controlled trial of hot water (45°C)
immersion versus ice packs for pain relief in bluebottle stings. Medical Journal of
Australia 2006; 184(7):329–333.
ENVENOMINGS
Tibballs J. Australian venomous jellyfish, envenomation syndromes, toxins and therapy.

Toxicon 2006; 48:830–859.
5.9 STONEFISH Distribution of stonefish species
• Synanceia trachynis
Brisbane
486 • Synanceia verrucosa
48
Stonefish are extremely well-camouflaged

6
reef fish found in the waters of northern

Australia. Their dorsal spines contain
TOXICOLOGY HANDBOOK
venom, which is injected when external

pressure is applied.
TOXINS
The venom contains pre- and
postsynaptic neurotoxins, vascular Geraldton
permeability factors, tissue necrosis
factors (hyaluronidase) and a
vasodilator (stonustoxin). Some
venom components may be denatured by heat.

• Immediate severe pain at the sting site.
• Local swelling, bruising and puncture marks. A remnant of the
spine(s) may be left in the wound.
• Systemic envenoming is rare and there are no reports of deaths
in Australia.
• Non-specific features of envenoming include nausea, vomiting,
dizziness and dyspnoea.
• Cardiovascular signs, such as hypotension, bradycardia, collapse,
pulmonary oedema and cyanosis, are rarely reported.
ERRNVPHGLFRVRUJ
MANAGEMENT
Pre-hospital
• Reassure the patient, and give simple oral analgesia such as
paracetamol.
• Immerse both limbs in hot water. The unaffected limb is immersed
to ensure the water temperature is tolerable and so prevent burns.
• Transport all patients with significant pain refractory to first aid or,
with systemic symptoms, to a medical facility.
Hospital
• Stonefish envenoming is very painful, but rarely life threatening.
• Treatment is essentially supportive.
• Continue hot water immersion.
• Give IV morphine 0.1 mg/kg (up to 5 mg), repeated every 10
minutes until patient is comfortable.
• Consider regional anaesthesia (e.g. foot block or wrist block) with
a long-acting local anaesthetic agent (e.g. ropivacaine).
ENVENOMINGS
Antivenom
• CSL Stonefish Antivenom (see Chapter 6.8) is used in the
treatment of severe pain refractory to first aid, IV opioid analgesia
and regional block and/or systemic envenoming.
• Give 1 ampoule (2000 units) for every two spine puncture wounds
(to a maximum of 3 ampoules), undiluted by IM injection or
diluted in 100 mL normal saline IV over 20 minutes.
487
INVESTIGATIONS
• Plain X-ray or ultrasound examination may assist detection of a
retained foreign body.
TOXICOLOGY HANDBOOK
• Other fish stings
• Stingray injury

• Patients without clinical features of systemic envenoming at
2 hours do not require further medical observation.
• Patients treated with opioid analgesia or antivenom may be
discharged when they have been asymptomatic for a period of
4 hours.
• Prior to discharge patients should be warned of the signs of
secondary infection.
HANDY TIPS
• Beware retained foreign bodies and marine infection.
• Hot water should not be used following local anaesthetic
infiltration because of the risk of thermal burn.
PITFALL
• Failure to administer antivenom when indicated.
ERRNVPHGLFRVRUJ
CONTROVERSIES
• It is not known whether stonefish antivenom is more efficacious
by the IV or IM route.
• Indications for antibiotics.
References
Lee JYL, Teoh LC, Leo SPM. Stonefish envenomation of the hand – a local marine
hazard. A series of 8 cases and review of the literature. Annals of the Academy of
Medicine Singapore 2004; 33:515–520.
Little M. Stonefish (Synanceia species) sting. Emergency Medicine 1990; 2(4):5.
Ngo SYA, Ong SHJ, Ponampalam R. Stonefish envenomation presenting to a Singapore
hospital. Singapore Medical Journal 2009; 50:506–509.
5.10 BOX JELLYFISH Distribution of box jellyfish
• Chironex fleckeri
ENVENOMINGS
Gladstone
The box jellyfish is found in tropical Exmouth
Australian waters. Most stings are
benign and respond to supportive
measures. Severe envenoming has
been associated with at least 70 deaths
in Australia, the last 12 being children.
Deaths occur within 5 minutes of the
488 sting, probably secondary to direct
48
cardiac toxicity.
8
TOXICOLOGY HANDBOOK
TOXINS
The specific venom components
are still being identified. The lethal
component appears to affect calcium channels. Pore formation on
cell membranes is associated with a rapid rise in cytosolic calcium
levels in myocytes. There are also haemolytic and dermatonecrotic
components.

• Stings are associated with immediate severe pain, typically
lasting up to 8 hours, and linear welts, which characteristically
occur in a crosshatched pattern.
• In 25–30% of cases the jellyfish tentacles are still
adherent.
• Systemic envenoming is heralded by collapse or sudden
death within a few minutes of the sting.
• Cardiovascular effects include hypertension, hypotension,
tachycardia, impaired cardiac contraction and
dysrhythmias.
• Delayed hypersensitivity reactions occur in at least 50% of
patients and manifest as pruritic erythema at the original sting
site, 7–14 days after the sting.
ERRNVPHGLFRVRUJ
MANAGEMENT
Pre-hospital
• If cardiac arrest occurs, it will happen on the beach. Immediate
and prolonged cardiopulmonary resuscitation is indicated.
• Reassure the conscious patient, apply an ice pack and give
simple oral analgesia such as paracetamol.
• Apply generous volumes of vinegar (acetic acid) to all visible sting
sites to inactivate undischarged nematocysts (sting cells).
• Do not apply a pressure bandaging with immobilisation (PBI) as
this may promote systemic envenoming.
• Transport all patients with pain refractory to first aid or, if
systemic symptoms, to a medical facility.
Hospital
• Rarely, box jellyfish envenoming is a life-threatening emergency.
• Patients should be managed in an area equipped for
include:
ENVENOMINGS
— Cardiac arrest
— Hypotension or hypertension
— Cardiac dysrhythmia.
• In cardiac arrest, undiluted antivenom, administered as a rapid IV
push, may be life saving. All immediately available Box Jellyfish
Antivenom (up to 6 ampoules) should be given. Intravenous
magnesium (10 mmol) should be given if no response to antivenom.
• Give titrated morphine (0.1 mg/kg IV up to 5 mg every 10 minutes) 489
to patients with pain refractory to first aid.
Antivenom
• CSL Box Jellyfish Antivenom (see Chapter 6.9) is the definitive
TOXICOLOGY HANDBOOK
treatment of envenoming by box jellyfish.
• Give 6 ampoules (6 × 20 000 units) as an IV push in
cardiorespiratory arrest.
• Give 3 ampoules (3 × 20 000 units) IV diluted in 100 mL normal
saline over 20 minutes to all patients with systemic envenoming
as evidenced by collapse, hypotension or significant cardiac
dysrhythmia. The patient is observed closely for response to
treatment and ongoing features of envenoming prompt a further
dose of antivenom (up to 3 ampoules).
• Give 1 ampoule (20 000 units) for pain refractory to IV opioid
analgesia.
INVESTIGATIONS
• Perform a 12-lead ECG to look for evidence of tachycardia, sinus
dysrhythmia, ventricular ectopic beats, bigeminy and bundle
branch blocks.
• Laboratory investigations are indicated to exclude alternative
diagnoses and assess complications in those patients who
present following collapse or cardiovascular instability.
• In the haemodynamically unstable patient, check FBC, EUC,
serum magnesium, serum calcium, serum phosphate, CK and
troponin and perform chest X-ray.
ERRNVPHGLFRVRUJ
• Bluebottle stings (Physalia spp.) are also associated with
immediate pain and dermal markings. Pain usually resolves within
1 hour and systemic symptoms are extremely rare.
• Pain associated with irukandji syndrome is usually delayed,
severe and generalised. Significant linear dermal markings or
welts are not seen.
• Decompression illness may lead to severe pain and collapse
shortly after a diver has surfaced. Local pain and welts are
not seen.

• Patients without clinical features of systemic envenoming or local
pain at 2 hours do not require further medical observation.
• Patients with severe pain who require opioid analgesia or
antivenom are discharged when asymptomatic for 6 hours.
• Envenomed patients treated with antivenom are also discharged
when asymptomatic for 6 hours.
ENVENOMINGS
HANDY TIPS
• Reassurance is important. Despite its reputation, the vast majority
of box jellyfish stings require only first aid and simple analgesia.
• Survival from cardiac arrest on the beach due to box jellyfish
envenoming has been reported following prompt and prolonged
CPR.
• Patients who die, do so at the scene of the sting. If they are alive
on arrival at hospital they will survive.
490
• A steroid or antihistamine cream may provide symptomatic relief if
49
a delayed hypersensitivity rash occurs.

0
• Immediate pain after a jellyfish sting, occurring in shallow tropical

TOXICOLOGY HANDBOOK
waters between November and April, associated with linear welts

with a cross-hatched pattern, is pathognomonic of Chironex
fleckeri sting.
PITFALLS
• Failure to commence immediate CPR when cardiac arrest occurs
on the beach.
• Administration of antivenom when not indicated.
CONTROVERSIES
• Efficacy and role of CSL Box Jellyfish Antivenom.
• Recent laboratory work has demonstrated increased venom
release from already discharged nematocysts following
application of vinegar. The first aid recommendations regarding
application of vinegar may need to be reconsidered.
• Ice is currently recommended as appropriate first aid. It is
possible that heat is more effective.
References
Currie BJ, Jacups S. Prospective study of Chironex fleckeri and other box jellyfish stings
in the ‘Top End’ of Australia’s Northern Territory. Medical Journal of Australia 2005;
183:161–166.
ERRNVPHGLFRVRUJ
Currie BJ. Marine antivenoms. Journal of Toxicology – Clinical Toxicology 2003;
41:301–308.
Tibballs J. Australian venomous jellyfish, envenomation syndromes, toxins and therapy.
Toxicon 2006; 48:830–859.
Welfare P, Little M, Pereira P, Seymour J. An in-vitro examination of the effect of vinegar
on discharged nematocysts of Chironex fleckeri. Diving and Hyperbaric Medicine
2014; 44(1):30–34.
5.11 IRUKANDJI SYNDROME Distribution of irukandji and

related jellyfish
Irukandji syndrome is a distressing
envenoming secondary to the sting of Moreton
Carukia barnesi and other, as yet Bay
unidentified, jellyfish found in coastal Exmouth
waters of tropical Australia. It has also
been reported in Hawaii, the Caribbean,
Asia and Papua New Guinea. In a small
ENVENOMINGS
number of cases, life-threatening
hypertension and pulmonary oedema
may develop. Two fatalities have been
attributed to this condition in Australia.
Management is symptomatic and
supportive. Antivenom has not yet
been developed.
TOXINS 491
Venom composition and actions have not been fully characterised. It
is thought to induce massive catecholamine release.
TOXICOLOGY HANDBOOK
• The initial sting is usually not felt and there is a short delay to the
onset of systemic symptoms. Local signs, such as welts or
dermal markings, are minimal or absent.
• Multiple systemic symptoms develop from 30 to 120 minutes after
contact with the jellyfish. These include a sense of impending
doom, agitation, dysphoria, vomiting, generalised sweating and
severe pain in the back, limbs or abdomen. Hypertension and
tachycardia are common.
• Symptoms usually settle within 12 hours.
• Severe envenoming manifests within 4 hours, with ongoing
significant opioid requirements. These patients are at risk of toxic
cardiomyopathy, cardiogenic shock and pulmonary oedema and
may require intubation and mechanical ventilation.
• Intracerebral haemorrhage occurred in two patients within 3–4
hours of the sting, possibly secondary to uncontrolled hypertension.
MANAGEMENT
Pre-hospital
• Apply generous volumes of vinegar to all visible sting sites to
inactivate all undischarged nematocysts (sting cells).
ERRNVPHGLFRVRUJ
• Transport all patients with pain refractory to first aid or, if
systemic symptoms, to a medical facility.
Hospital
• This is a potentially life-threatening emergency. Patients should
be managed in an area equipped for cardiorespiratory monitoring
and resuscitation.
include:
— Severe hypertension
— Pulmonary oedema.
• Administer IV fentanyl (0.5–1.0 microgram/kg/dose) repeated
every 10 minutes until appropriate analgesia is achieved. Large
doses may be required (e.g. 200–300 micrograms). Note: If
fentanyl is not available, give morphine 0.05–0.1 mg/kg IV in
titrated doses.
• Treat nausea with IV promethazine (25 mg; 0.5 mg/kg in
children).
ENVENOMINGS
• Control hypertension refractory to opioid analgesia with an

intravenous infusion of glyceryl trinitrate (GTN 50 mg in
100 mL starting at 6 mL/minute; 1–4 microgram/kg/minute
in children) titrated to achieve a systolic blood pressure
<160 mmHg.
Antivenom
• None available.
492
49
INVESTIGATIONS
2

diagnoses and to assess complications in those patients who
TOXICOLOGY HANDBOOK
present following collapse or cardiovascular instability.

• Perform a 12-lead ECG to look for evidence of tachycardia,
ischaemia and non-specific T wave conduction abnormalities.
• Perform a chest X-ray in patients with ongoing opioid
requirements or clinical evidence of pulmonary oedema.
• In the haemodynamically unstable patient check FBC, EUC, ECG,
troponin and CK every 8 hours.
• Echocardiography is indicated in patients with pulmonary oedema
or hypotension requiring inotropic support.
with immediate pain and obvious dermal markings (large welts).
Tentacles may be seen adherent to the skin.
• Bluebottle stings (Physalia spp.) are associated with immediate
pain and dermal markings. The pain usually resolves within 1 hour
and systemic symptoms are extremely rare.
• Decompression illness may lead to generalised pain or
collapse shortly after a diver has surfaced. Welts are
not seen.
ERRNVPHGLFRVRUJ
• Redback spider envenoming (Latrodectus hasselti) causes bite
site pain and sweating, followed by more generalised pain,
sweating and dysphoria. It is associated with contact with a
spider on land.

• Patients without features of systemic envenoming at 2 hours do
not have irukandji syndrome and do not require medical
observation.
• Patients with severe pain who require opioid analgesia may be
discharged when they are clinically well and pain-free for a period
of 6 hours.
HANDY TIPS
• Clinical features of envenoming occur after the patient has left the
water, so they may be unaware they have been stung.
• Irukandji syndrome should be considered in any patient
presenting with clinical features during or shortly after swimming
in tropical coastal Australian waters.
ENVENOMINGS
• Clinical features of dysphoria, severe generalised pain,
sweating, hypertension and pulmonary oedema, in the absence
of major dermal findings, are pathognomonic of irukandji
syndrome.
• Patient-controlled analgesia may be useful if there is ongoing
opioid requirement.
PITFALLS
493
• Failure to recognise the potential for irukandji syndrome.
• Failure to administer adequate opioid analgesia.
• Failure to consider the potential for development of
TOXICOLOGY HANDBOOK
cardiomyopathy.
CONTROVERSIES
• Magnesium IV has been advocated for control of pain refractory
to opioid administration. This practice is as yet unsupported by
clinical trials.
• Recent laboratory work has demonstrated increased venom
release from already discharged nematocysts following
application of vinegar. The first aid recommendations regarding
application of vinegar may need to be reconsidered.
• The role of benzodiazepines in the management of symptoms is
presumed to be due to catecholamine release.
• The agent of choice to manage hypertension and tachycardia.
References
Barnes JH. Cause and effect in Irukandji stingings. Medical Journal of Australia 1964;
1:897–904.
Huynh TT, Seymour J, Pereira P et al. Severity of Irukandji syndrome and nematocyst
identification from skin scrapings. Medical Journal of Australia 2003; 178:38–41.
Little M, Mulcahy RF. A year’s experience of ‘Irukandji’ jellyfish envenomation in far north
Queensland. Medical Journal of Australia 1998; 169:638–641.
ERRNVPHGLFRVRUJ
Little M, Pereira P, Carrette T et al. Jellyfish responsible for irukandji syndrome.
Quarterly Journal of Medicine 2006; 99:425–427.
Macrocanis CJ, Hall NJ, Mein JK. Irukandji syndrome in northern Western Australia:
an emerging health problem. Medical Journal of Australia 2004; 181(11/12):
699–702.
McCullagh N, Pereira P, Cullen P et al. Randomised trial of magnesium in the
treatment of Irukandji syndrome. Emergency Medicine Australasia 2012;
24(5):560–565.
Nickson CP, Waugh EB, Jacups SP et al. Irukandji syndrome case series from
Australia’s tropical Northern Territory. Annals of Emergency Medicine 2009;
54(3):395–403.
5.12 BLUE-RINGED OCTOPUS

• Hapalochlaena lunulata: northern or greater blue-ringed octopus
• Hapalochlaena maculosa: southern or lesser blue-ringed octopus
This small octopus is found in shallow coastal waters around Australia.
They are not aggressive and bites usually occur when humans ‘play’ with
this animal. Envenoming causes rapid paralysis. Timely support of airway
ENVENOMINGS
and ventilation ensures a good outcome.
TOXINS
Tetrodotoxin (maculotoxin in Hapalochlaena maculosa) is a potent
sodium channel blocking neurotoxin. Venom is produced by bacteria
in the salivary glands and introduced from the beak under the body of
the octopus, not from the tentacles.
494
49

4
• The bite may not be painful.

•
TOXICOLOGY HANDBOOK
Local symptoms are minimal or absent.

• Systemic envenoming is characterised by a rapidly progressive
symmetrical descending flaccid paralysis, which usually manifests
within minutes.
• Early signs include ptosis, blurred vision, diplopia and
difficulty swallowing. If left untreated, generalised paralysis,
respiratory failure and secondary hypoxic cardiac arrest
ensue.
• With the institution of advanced airway support, paralysis resolves
spontaneously within 24 hours.
MANAGEMENT
Pre-hospital
• Commence expired air respiration (EAR) if required.
Hospital
• Blue-ringed octopus envenoming is potentially life threatening.
Patients should be managed in an area equipped for
ERRNVPHGLFRVRUJ
include:
— Descending flaccid paralysis with respiratory failure
— Hypotension.
• If respiratory failure is present, provision of an airway and
mechanical ventilation is life saving.
Antivenom
• None available.
INVESTIGATIONS
diagnoses and assess complications.
• Spirometry or peak flow measurements are useful to monitor
respiratory function.
with collapse on the beach and sudden death following a sting.
However, there is immediate severe pain and obvious dermal
ENVENOMINGS
markings (large welts). Tentacles may be seen adherent to
the skin.
• Puffer fish also contain tetrodotoxin and ingestion of these fish
can lead to flaccid paralysis. The history usually permits this
diagnosis to be easily distinguished from blue-ringed octopus bite.

• Patients who are not envenomed will have no clinical features of 495
paralysis at 6 hours and may be discharged. Discharge should
not occur at night.
• Envenomed patients with paralysis require ventilatory support and
TOXICOLOGY HANDBOOK
admission to intensive care.
HANDY TIP
• Collapse with paralysis, on or near the beach, shortly after a
minor bite is pathognomonic of blue-ringed octopus envenoming.
— Remember that patients remain conscious after paralysis has
occurred if no sedation is administered.
PITFALLS
• Failure to appreciate the importance of close observation during
the first few hours.
• Failure to appreciate that the paralysed patient is fully aware
unless sedated.
References
Cavazzoni, E, Lister B, Sargent P, Schibler A. Blue-ringed octopus (Hapalochlaena sp.)
envenomation of a 4-year-old boy: a case report. Clinical Toxicology 2008;
46:760–761.
Sutherland SK, Lane WR. Toxins and mode of envenomation of the common ringed or
blue-banded octopus. Medical Journal of Australia 1969; 1:893–898.
ERRNVPHGLFRVRUJ
5.13 REDBACK SPIDER Distribution of redback spiders
• Latrodectus hasselti: redback

spider (Australia)
• Latrodectus katipo: katipo
spider (New Zealand)
Redback spider bite is the most
common medically significant
envenoming in Australia, with
5000–10 000 human bites occurring
annually. Clinical features can be
distressing and refractory to
symptomatic treatment, but are not
life threatening.
TOXINS
Venom of the Latrodectus genus contains alpha-latrotoxin. This toxin
ENVENOMINGS
acts presynaptically to open cation channels (including calcium

channels) and stimulate the release of multiple motor end-plate
neurotransmitters.

• Redback spider bites are not immediately painful.
• Intense local pain develops 5–10 minutes after the bite and is
496 followed by sweating and piloerection within an hour. Puncture
marks are not always evident and erythema, if present, is
49
usually mild.
6
• Systemic envenoming occurs in a significant minority of patients.

TOXICOLOGY HANDBOOK
Pain typically radiates proximally from the bite site to become

regional, then general (e.g. pelvic, back, abdominal, chest or
shoulder pain). Autonomic features include severe sweating,
which may be regional (e.g. both legs) or generalised, mild
hypertension and tachycardia.
• Non-specific features of envenoming include headache, nausea,
vomiting and dysphoria.
• Untreated, systemic envenoming may follow a fluctuating course
lasting 1–4 days. Rarely, patients may feel unwell for up to 1
week. Very rarely, patients report ongoing local symptoms that
last weeks or months.
MANAGEMENT
Pre-hospital
• Do not apply a pressure bandage with immobilisation
(PBI).
• Refer to hospital if the patient has local symptoms refractory to
simple analgesia, clinical features of systemic envenoming or the
diagnosis is in doubt.
ERRNVPHGLFRVRUJ
Hospital
• Redback spider envenoming is not life threatening and
resuscitation is not required.
Antivenom
• CSL Redback Spider Antivenom (see Chapter 6.10) has for many
years been regarded as the specific treatment for moderate-to-
severe pain and/or systemic symptoms of lactrodectism; however,
its clinical utility has recently been questioned (see Controversy
below).
• The standard dose is 2 ampoules (2 × 500 units) IV.
INVESTIGATIONS
• Laboratory investigations do not assist in diagnosis or
management.
• Funnel-web spider envenoming is potentially lethal. It is
associated with immediate bite site pain, visible fang marks and
ENVENOMINGS
the abrupt onset, within minutes, of a severe clinical syndrome
characterised by sweating, agitation, piloerection, cardiovascular
and neurological changes.
• Envenoming by Steatoda species (cupboard spider or
brown house spider) closely resembles redback spider
envenoming.
• Non-specific spider bites are associated with bite site pain and
mild systemic symptoms, such as nausea, headache, malaise or 497
• Latrodectism has been mistaken for conditions such as acute
TOXICOLOGY HANDBOOK
surgical abdomen, acute myocardial infarction and thoracic aortic
dissection.

• Patients without clinical features of systemic envenoming or local
pain do not require referral for medical evaluation.
• Envenomed patients may be discharged when asymptomatic or if
symptoms have improved, and advised to return if symptoms
remain debilitating.
HANDY TIPS
• The triad of local pain, sweating and piloerection increasing over
the first hour is pathognomonic of redback spider bite.
• Profuse symmetrical sweating and pain in both lower limbs is also
a characteristic clinical presentation of latrodectism.
• Consider the diagnosis in any child with abrupt onset of
inconsolable crying, abdominal pain or priapism.
PITFALL
• Failure to consider the diagnosis when spider bite is not
witnessed.
ERRNVPHGLFRVRUJ
CONTROVERSY
• The clinical value of antivenom administration in the management
of latrodectism has recently been questioned with a randomised
controlled study in adults (RAVE II) suggesting that it does not
provide significant clinical benefit above that of standard
analgesia in control of the pain and systemic symptoms of
redback envenoming.
References
Isbister GK, Brown SGA, Miller M et al. A randomised controlled trial of intramuscular
versus intravenous antivenom for latrodectism – the RAVE study. Quarterly Journal
of Medicine 2008; 101:557–565.
Isbister GK, Gray MR. Latrodectism: A prospective cohort study of bites by formally
identified redback spiders. Medical Journal of Australia 2003; 179:88–91.
Isbister GK, O’Leary MA, Miller M et al. A comparison of serum antivenom concentrations
after intravenous and intramuscular administration of redback (widow) spider
antivenom. British Journal of Clinical Pharmacology 2008; 65:138–143.
Isbister GK, Page CB, Buckley NA et al. Randomised controlled trial of intravenous
antivenom versus placebo for lactrodectism: the second redback antivenom
evaluation (RAVE II) study. Annals of Emergency Medicine 2014; 64:1–9 (In press).
ENVENOMINGS
Isbister GK, Sibbritt D. Developing a decision tree algorithm for the diagnosis of
suspected spider bites. Emergency Medicine Australia 2006; 16:161–166.
5.14 FUNNEL-WEB (BIG Distribution of funnel-web spiders

BLACK) SPIDER
Mountain region
near Mossman
• Atrax robustus: Sydney funnel-web
Gladstone
498 spider
• Hadronyche cerberea: southern tree
49
8
funnel-web spider
• Hadronyche formidabilis: northern
TOXICOLOGY HANDBOOK
tree funnel-web spider

• Hadronyche infensa: Toowoomba or
Darling Downs funnel-web spider
• Hadronyche species 14: Port
Macquarie funnel-web spider
• Hadronyche versuta: Blue Mountains
funnel-web spider
Tamworth
The funnel-web spiders (FWS) comprise Albury
40 species in two genera (Atrax and
Hadronyche). These potentially lethal
spiders look very similar to other medically less significant big black
spiders, including the trap door spiders (families Idiopidae and
Nemesiidae) and mouse spiders (Actinopididae). For this reason it is
important to have a clinical approach to bite by a big black spider within
the distribution of the FWS.
TOXINS
Both genera of FWS produce venom that contains potent
neurotoxins. Robustoxin (Atrax sp.) and versutoxin (Hadronyche sp.)
prevent inactivation of sodium channels, leading to a massive
increase in autonomic activity and neuromuscular excitation.
ERRNVPHGLFRVRUJ
• The patient often gives a history of witnessed painful bite by a big
black spider with large fangs.
• Local pain at the bite site is severe and fang marks are often
visible.
• Local erythema and swelling are not features of FWS bite.
• Severe systemic envenoming, if it occurs, develops rapidly,
usually within 30 minutes and almost always within 2 hours.
Clinical features include:
— General – agitation, vomiting, headache and abdominal pain
— Autonomic – sweating, salivation, piloerection and lacrimation
— Cardiovascular – hypertension, tachycardia, hypotension,
bradycardia and pulmonary oedema
— Neurological – muscular fasciculation, oral paraesthesia,
muscle spasm and coma.
• In young children, the first indication of envenoming may be
sudden severe illness with inconsolable crying, salivation,
vomiting or collapse.
ENVENOMINGS
MANAGEMENT
Pre-hospital
• Transport to a hospital capable of providing definitive care
(antivenom, resuscitation facilities and medical staff).
Hospital
• Funnel-web spider envenoming is potentially life threatening. 499
Patients are managed in an area equipped for cardiorespiratory
TOXICOLOGY HANDBOOK
include:
— Respiratory failure
— Hypotension or hypertension
— Pulmonary oedema
— Coma.
• In cardiac arrest, undiluted antivenom, administered as a rapid IV
push, may be life-saving. All immediately available funnel-web
antivenom (at least 4 ampoules) should be given.
• Atropine may help decrease secretions until antivenom can be
administered.
Antivenom
• CSL Funnel-web Spider Antivenom (see Chapter 6.11) is the
specific treatment of envenoming by FWS.
• Give an initial dose of 2 ampoules (2 × 125 units) to all patients
with systemic envenoming as evidenced by neurological,
autonomic or cardiovascular features.
• The patient is observed for response to treatment. Ongoing
features of envenoming prompt administration of a further dose of
2 ampoules of antivenom.
• An initial dose of 4 ampoules may be indicated in the severely
envenomed patient.
ERRNVPHGLFRVRUJ
INVESTIGATIONS
diagnoses and to assess complications in severe envenoming.
• Redback spider envenoming is characterised by a triad of
local pain, sweating and piloerection. Systemic features
include generalised pain, sweating and dysphoria. Lethal
envenoming with coma, fasciculation or pulmonary oedema
does not occur.
• Bites by the other big black spiders (trap door and mouse
spiders) may be associated with significant bite site pain but only
mild systemic symptoms, such as nausea, headache, malaise or
• Scorpion stings cause local pain and paraesthesia without
evidence of systemic envenoming.

ENVENOMINGS
• Patients without clinical features of systemic envenoming at 4

hours do not require further medical management.
• Envenomed patients treated with antivenom are discharged if
clinically well for 12 hours. Do not discharge at night.
HANDY TIPS
• Big black spider bite in New South Wales or southern Queensland
500 is assumed to be by a FWS until proven otherwise.
• Removal of PBI only occurs when the patient is located in an area
50
0
equipped for cardiorespiratory resuscitation with adequate

supplies of FWS antivenom.
TOXICOLOGY HANDBOOK
• A painful bite by a big black spider, with abrupt onset of

sweating, agitation, piloerection, coma and fasciculations is
pathognomonic of FWS envenoming.
PITFALLS
• Failure to consider the diagnosis when spider bite is not
witnessed.
• Failure to anticipate the abrupt onset of life-threatening
envenoming and that delayed envenoming may occur following
the release of PBI.
• Removal of PBI prior to availability of antivenom and resuscitation
facilities.
References
Isbister GK, Gray MR, Balit CR et al. Funnel-web spider bite: a systematic review of
recorded clinical cases. Medical Journal of Australia 2005; 182:407–411.
Isbister GK, Sibbritt D. Developing a decision tree algorithm for the diagnosis of
suspected spider bites. Emergency Medicine Australasia 2006; 16:161–166.
Nicholson GM, Graudins A, Wilson HI et al. Arachnid toxinology in Australia: from clinical
toxicology to potential applications. Toxicon 2006; 48:872–898.
Rosengren D, White J, Raven R et al. First report of a funnel-web spider envenoming
syndrome in Brisbane. Emergency Medicine Australasia 2008; 20:164–166.
ERRNVPHGLFRVRUJ
5.15 WHITE-TAILED SPIDER
• Lampona cylindrata
• Lampona murina
The white-tailed spider is ubiquitous throughout Australia and previously
believed to cause necrotic arachnidism, a syndrome of progressive
cutaneous injury from spider venom. This association has now been
refuted.
TOXINS
The venom of Lampona cylindrata has been extensively studied. No
cytotoxic effects have been noted.

• Painful bite.
• Three local reactions to bites from Lampona species are
reported:
ENVENOMINGS
— Severe local pain of <2 hours duration
— Local pain and a red mark lasting <24 hours
— A persistent and painful red lesion, which does not break
down or ulcerate, and may last 5–12 days.
• Mild, non-specific features of envenoming include nausea,
vomiting, malaise and headache.
• Delayed pruritus occurs in up to 20% of cases.
• No ulcers, necrotic lesions or infections were identified in a
prospective study of 130 Lampona bites, where the spider was 501
caught and formally identified by an arachnidologist.
MANAGEMENT
TOXICOLOGY HANDBOOK
• Referral to hospital is not indicated.
INVESTIGATIONS
• Investigations are required only in an attempt to establish an
alternative diagnosis for a chronic skin lesion. These might include
skin biopsy and microbiological investigations.
• If a necrotic cutaneous lesion is present, a causal association with
a spider bite is a diagnosis of exclusion.
• The differential diagnoses of a chronic skin ulcer include:
— Infections (staphylococcal, streptococcal, herpes simplex,
herpes zoster, gonococcal, mycobacterial, fungal)
— Diabetic ulcers
— Pyoderma gangrenosum
— Squamous cell carcinoma
— Erythema nodosum
— Chemical burn
ERRNVPHGLFRVRUJ
— Lymphomatoid papulosis
— Localised vasculitis
— Factitious injury
— Traumatic.

• Patients with an idiopathic non-specific chronic cutaneous ulcer
may be discharged to the care of their general practitioner for
further investigation or referred to a dermatologist as appropriate.
PITFALL
• Attribution of causation of a chronic ulcer to spider bite in
Australia without extensive investigation to exclude alternative
diagnosis.
References
Isbister GK, Gray MR. White-tailed spider bite: a prospective series of 130 definite bites
by the Lampona species. Medical Journal of Australia 2003; 179:199–202.
Swanson DL, Vetter RS. Bites of the brown recluse spiders and suspected necrotic
ENVENOMINGS
arachnidism. New England Journal of Medicine 2005; 352:700–707.
5.16 TICKS Distribution of Ixodes hylocyclus
• Ixodes cornuatus Cairns

• Ixodes hirsti
502
• Ixodes holocyclus
Ticks are arachnids that attach to other
50
2
animals at various stages of their life

cycles and obtain blood for nourishment.
TOXICOLOGY HANDBOOK
There are 70 tick species found in

Australia, but only the three Ixodes
species listed above cause paralysis.
Tick paralysis in humans is almost
exclusively associated with Ixodes Bairnsdale
holocyclus, distributed in a narrow
eastern coastal strip extending from far
north Queensland to Victoria.
TOXINS
The salivary glands of ticks excrete multiple haemostatic and
anti-inflammatory agents to facilitate attachment and feeding. These
include, in the case of the adult female Ixodes holocyclus, a protein
neurotoxin known as holocyclotoxin. It is thought to act at the
presynaptic region of the neuromuscular junction and inhibit release
of acetylcholine.

• Tick paralysis, although rare, is the most feared complication of
tick bite. It usually occurs in children under 3 years of age, but
has been reported in adults.
ERRNVPHGLFRVRUJ
• Tick paralysis presents as a non-specific prodrome that includes
drowsiness and unsteadiness of gait. This may be followed by a
progressive ascending symmetrical flaccid paralysis that can take
days to develop. Cranial nerves are frequently involved leading to
ocular paralysis, ptosis and facial paralysis.
• Paralysis may progress for up to 48 hours after the tick is
removed or falls off.
• Death, if it occurs, is from respiratory paralysis.
• Recovery in survivors is slow and it may take several weeks
before strength returns to normal.
• Non-paralytic complications of tick bite include local itching and
swelling, hypersensitivity reactions and local granuloma formation
due to retention of mouth parts.
• A number of human infections are transmitted by ticks, but these
are outside the scope of this book.
MANAGEMENT
Pre-hospital
• The diagnosis of tick paralysis is rarely considered in the
ENVENOMINGS
pre-hospital phase. Respiration should be supported if necessary.
Hospital
• Tick paralysis is potentially life threatening, the major threat being
respiratory failure.
• Patients should be managed in an area equipped for
• If respiratory failure develops, provision of an airway and 503
mechanical ventilation is life saving.
• If mechanical ventilation is required, it is likely to be required for
days to weeks.
TOXICOLOGY HANDBOOK
Tick removal
• The tick should be located and removed as soon as practicable.
• When the diagnosis of tick paralysis is considered, a careful
search for ticks should include the scalp, behind the ears, inside
the auditory canal, the nose, perineum and natal cleft.
• When located, the tick is carefully removed with every attempt
made to remove all of the tick mouth parts attached to the skin.
The tick should be grasped as close to the skin as possible using
fine forceps, veterinary tick removers or a loop of dental floss or
suture material. Once grasped, the tick is then removed by
applying gentle outward traction.
Antivenom
• None available for human use.
INVESTIGATIONS
• Tick paralysis is a clinical diagnosis. Investigations are directed at
excluding alternative diagnoses.
• Nerve conduction studies, if performed, are abnormal with
reduced amplitude of compound motor action potentials but
normal conduction velocities. Sensory nerve studies are normal.
ERRNVPHGLFRVRUJ
• This history of tick bite is frequently not available. The major
differential diagnosis of ascending flaccid paralysis is Guillain-
Barré syndrome. Location of an engorged paralysis tick by careful
searching will confirm the diagnosis of tick paralysis. Ocular signs
are not a feature of Guillain-Barré syndrome.
• Infant botulism produces a similar clinical picture, but usually
occurs in the first few months of life, whereas tick paralysis
usually occurs in older more mobile children.
• Paralysis also occurs after snake and blue-ringed octopus
envenoming, but the progression in those cases is always much
more rapid than that seen in tick paralysis.

• All patients must be admitted for close, sequential neurological
observation.
• Discharge should not occur until sustained neurological
improvement is documented.
• Patients requiring ventilatory support should be managed in an
ENVENOMINGS
intensive care unit. Several days to 1 week of ventilation followed

by several weeks of convalescence can be anticipated.
HANDY TIPS
• Consider the diagnosis of tick paralysis in any young child who
develops weakness or difficulty walking and resides on or has
recently visited the east coast of Australia.
504 • Consideration of the diagnosis should always prompt a careful
search for an attached tick.
50
• The attached tick will usually be located on the head, frequently

4
in the scalp above the hairline or behind the ears.

•
TOXICOLOGY HANDBOOK
More than one tick may be attached.

• Weakness can be expected to progress for up to 48 hours after
removal of the tick.
PITFALL
• Failure to admit the symptomatic child to hospital for continued
observation after removal of the tick.
CONTROVERSY
• It has been suggested that forcible removal of a live tick will
cause release of further toxin. It has been advocated that the tick
should be killed using a pyrethrin-based insecticide prior to
removal but the value of this practice is unsubstantiated.
References
Edlow JA, McGillicuddy DC. Tick paralysis. Infectious Disease Clinics of North America
2008; 22:397–413.
Grattan-Smith PJ, Morris JG, Johnston HM et al. Clinical and neurophysiological features
of tick paralysis. Brain 1997; 120:1975–1987.
ERRNVPHGLFRVRUJ
CHAPTER 6
ANTIVENOMS
6.1 CSL Black Snake Antivenom 506

6.2 CSL Brown Snake Antivenom 507
6.3 CSL Death Adder Antivenom 509
6.4 CSL Tiger Snake Antivenom 511
6.5 CSL Taipan Antivenom 513
6.6 CSL Sea Snake Antivenom 515
6.7 CSL Polyvalent Snake Antivenom 517
6.8 CSL Stonefish Antivenom 519
6.9 CSL Box Jellyfish Antivenom 520
6.10 CSL Redback Spider Antivenom 522
6.11 CSL Funnel-web Spider Antivenom 524
ERRNVPHGLFRVRUJ
6.1 CSL BLACK SNAKE ANTIVENOM
This equine IgG Fab is the specific treatment of envenoming by black
snakes in Australia and Papua New Guinea. These include the mulga
snake (Pseudechis australis), Butler’s mulga snake (Pseudechis butleri),
Collett’s snake (Pseudechis colletti), Papuan black snake (Pseudechis
papuanus), red-bellied black snake (Pseudechis porphyriacus) and
blue-bellied black snake (Pseudechis guttatus).
PRESENTATION
18 000 unit (43–50 mL) ampoules
INDICATIONS
• Clinical evidence of systemic envenoming (see Chapter 5.1:
Black Snake)
• Laboratory evidence of anticoagulant coagulopathy
• Laboratory evidence of myotoxicity (CK >1000 IU/L)
CONTRAINDICATIONS
• Increased risk of anaphylaxis in patients who have been
ANTIVENOMS
previously treated with antivenom or who have a known or

suspected equine sera allergy
ADMINISTRATION
and personnel are available to manage an allergic reaction.
• Administer 1 ampoule diluted in 500 mL of normal saline IV over
506 20 minutes.
• Pre-medication with adrenaline is unnecessary.
50
• Re-check the coagulation profile and CK 12 hours after antivenom

6
administration.
TOXICOLOGY HANDBOOK

• Resolution of systemic features of envenoming, including
non-specific symptoms such as headache, abdominal pain and
vomiting
• Improving laboratory values that indicate a resolving coagulopathy
and falling CK
ADVERSE DRUG REACTIONS AND MANAGEMENT

Acute allergic or anaphylactic reaction
• Incidence is approximately 30%.
• Usually mild and manifested by erythema or urticaria. Severe
cases manifest with hypotension.
• Immediately cease antivenom infusion.
• Give oxygen, IV fluids and administer IM adrenaline 0.01 mg/kg
(max 0.5 mg) to lateral thigh (see Appendix 6 for full management
description).
• Recommence antivenom infusion cautiously when clinical
manifestations of anaphylaxis are controlled.
ERRNVPHGLFRVRUJ
• Note: Rarely, ongoing administration of adrenaline by titrated
infusion may be necessary to complete antivenom administration.
Serum sickness
• This relatively benign and self-limiting complication may occur
5–10 days after antivenom.
• Manifestations include fever, rash, arthralgia and myalgia.
• Oral steroids (e.g. prednisolone 50 mg/day in adults or 1–2 mg/
kg/day in children for 5 days) ameliorate symptoms.
• Note: All patients should be warned about this potential
complication prior to discharge.
Paediatric: give standard adult dose in 10 mL/kg of normal saline.
HANDY TIP
• If Black Snake Antivenom is not readily available, one ampoule of
Polyvalent Snake Antivenom may be substituted.
PITFALLS
• Withholding antivenom from the envenomed child or pregnant
ANTIVENOMS
woman because of concerns about the potential adverse reactions.
• Administration of antivenom to a patient who has not been
envenomed.
CONTROVERSIES
• There is debate regarding the indications for early administration
of antivenom to patients with mild systemic symptoms only in an
attempt to prevent subsequent myolysis.
507
• Tiger Snake Antivenom has been recommended as an alternative
to Black Snake Antivenom in the treatment of envenoming by the
red-bellied or blue-bellied black snake. It appears to be equally
effective and has the advantages of being more widely available, TOXICOLOGY HANDBOOK
cheaper and of smaller volume.
References
Churchman A, O’Leary MA, Buckley NA et al. Clinical effects of red-bellied black snake
(Pseudechis porphyriacus) envenoming and correlation with venom concentrations:
193:696–700.
Johnston CI, Brown SGA, O’Leary MA et al. Mulga snake (Pseudechis australis)
envenoming: a spectrum of myotoxicity, anticoagulant coagulopathy, haemolysis
and the role of early antivenom therapy – Australian Snakebite Project (ASP-19).
6.2 CSL BROWN SNAKE ANTIVENOM

This equine IgG Fab is the specific treatment of envenoming by brown
snakes in Australia. These include the eastern brown snake (Pseudonaja
ERRNVPHGLFRVRUJ
textilis), western brown snake or gwardar (Pseudonaja mengdeni), dugite
(Pseudonaja affinis) and other Pseudonaja species.
PRESENTATION
1000 unit (4.5–9 mL) ampoules
INDICATIONS
• Clinical evidence of systemic envenoming (see Chapter 5.2:
Brown snake)
• Laboratory evidence of complete or partial venom-induced
consumptive coagulopathy (VICC)
CONTRAINDICATIONS
ADMINISTRATION
ANTIVENOMS
20 minutes.
• Note: Antivenom may be given as a rapid IV push if the patient is
unstable or in cardiac arrest.

508 • Resolution of systemic features of envenoming
50
8

TOXICOLOGY HANDBOOK

description).
Serum sickness
• Oral steroids (e.g. prednisolone 50 mg/day or 1–2 mg/kg/day in
children for 5 days) ameliorate symptoms.
ERRNVPHGLFRVRUJ
PITFALLS
envenomed.
CONTROVERSIES
• There have been conflicting opinions regarding antivenom dosing.
Recent evidence from in vitro and clinical studies supports that a
single ampoule is sufficient and that recovery and outcome are
not improved with administration of more than one ampoule.
• Recent evidence has determined that administration of antivenom
does not hasten recovery from VICC. It may, however, reverse or
ANTIVENOMS
defined.
References
Allen GE, Brown SCA, Buckley NA et al. Clinical effects and antivenom dosing in brown
snake (Pseudonaja spp.) envenoming – Australian Snakebite Project (ASP-14). PLoS
ONE 2012; 7(12): e53188. doi:10.1371/journal.pone.0053188.
Brown SGA, Caruso N, Borland M et al. Clotting factor replacement and recovery from
509
35(9):1532–1538.
plasma for treating venom-induced consumption coagulopathy in cases of Australian TOXICOLOGY HANDBOOK
Isbister GK, Brown SG, MacDonald E et al. Current use of Australian snake antivenoms
and frequency of immediate-type hypersensitivity reactions and anaphylaxis. Medical
102(8):563–568.
6.3 CSL DEATH ADDER ANTIVENOM

This equine IgG Fab is the specific treatment of envenoming by the
death adder (Acanthophis spp.) in Australia and Papua New Guinea.
PRESENTATION
6000 unit (25 mL) ampoules
ERRNVPHGLFRVRUJ
INDICATIONS
• Clinical evidence of systemic envenoming, characterised by
progressive paralysis and the absence of coagulopathy (see
Chapter 5.3: Death adder)
CONTRAINDICATIONS
ADMINISTRATION
drugs and personnel are available to manage an allergic
reaction.
20 minutes.
• Observe the patient clinically and monitor serial spirometry/peak
flow measurements.

ANTIVENOMS
• Resolution of systemic features of envenoming

510 • Immediately cease antivenom infusion.
51
0

TOXICOLOGY HANDBOOK
description).
infusion may be necessary to complete antivenom
administration.
Serum sickness
ERRNVPHGLFRVRUJ
HANDY TIPS
• If Death Adder Antivenom is not available, 1 ampoule of
Polyvalent Antivenom may be substituted.
• If no antivenom is available, patients should be managed with
supportive care. Providing airway and ventilation are supported,
survival rates are high, with the symptoms of neurotoxicity
resolving within 36–48 hours.
PITFALLS
envenomed.
CONTROVERSY
• Relative efficacy of neostigmine as an alternative to antivenom.
References
Johnston CI, O’Leary MA, Brown SCA et al. Death adder envenoming causes
ANTIVENOMS
neurotoxicity not reversed by antivenom – Australian Snakebite Project (ASP-16).
PLoS Neglected Tropical Diseases 2012; 6(9):e1841
6.4 CSL TIGER SNAKE ANTIVENOM

This equine IgG Fab is the specific treatment of envenoming by tiger 511
snakes in Australia. These include the common tiger snake (Notechis
scutatus), western tiger snake (Notechis scutatus (ater) occidentalis),
Stephen’s banded snake (Hoplocephalus stephensii), pale-headed snake TOXICOLOGY HANDBOOK
(Hoplocephalus bitorquatus), broad-headed snake (Hoplocephalus
bungaroides), rough-scaled snake (Tropidechis carinatus) and
copperhead snakes (Austrelaps spp.). It is also used to treat envenoming
by the small-eyed snake (Cryptophis nigrescens).
PRESENTATION
3000 unit (9–12 mL) ampoules
INDICATIONS
• Clinical or laboratory evidence of systemic envenoming (see
Chapter 5.4: Tiger snake group)
• Tiger snake and rough-scaled snake: complete or partial
venom-induced consumptive coagulopathy (VICC), neurotoxicity
and myotoxicity
• Copperhead: paralysis and occasionally myotoxicity
• Pale-headed and broad-headed snake: VICC but not paralysis or
myotoxicity
• Small-eyed snake: myotoxicity
ERRNVPHGLFRVRUJ
CONTRAINDICATIONS
ADMINISTRATION
20 minutes.

• Note: Although Tiger Snake Antivenom halts the progression
of paralysis, established neurotoxicity is not reversed by
antivenom.

ANTIVENOMS

description).
512 manifestations of anaphylaxis are controlled.
51
2

administration.
TOXICOLOGY HANDBOOK
Serum sickness
HANDY TIP
• If the correct choice of monovalent antivenom cannot be assured
based on geography or SVDK testing, one vial of both Brown and
Tiger Snake Antivenoms should be given.
ERRNVPHGLFRVRUJ
PITFALLS
woman because of concerns about the potential adverse
reactions.
envenomed.
CONTROVERSIES
• Envenoming by Hoplocephalus spp. resembles that of brown
snake more than that of the tiger snake group. Tiger antivenom is
recommended but it is possible that brown snake antivenom may
be equally effective.
defined.
ANTIVENOMS
References
35(9):1532–1538.
plasma for treating venom-induced consumption coagulopathy in cases of Australian 513
102(8):563–568. TOXICOLOGY HANDBOOK
Isbister GK, O’Leary MA, Eliott M, Brown SGA. Tiger snake (Notechis spp.) envenoming:
197(3):173–177.
Isbister GK, White J, Currie BJ et al. Clinical effects and treatment of envenoming by
Hoplocephalus spp. snakes in Australia: Australian Snakebite Project (ASP-12).
Toxicon 2011; 58:634–640.
6.5 CSL TAIPAN ANTIVENOM

This equine IgG Fab is the definitive specific treatment of envenoming by
taipans in Australia and Papua New Guinea. These include the coastal
taipan (Oxyuranus scutellatus), the Papuan taipan (Oxyuranus scutellatus
canni) and the small-scaled or fierce snake (Oxyuranus microlepidotus).
PRESENTATION
12 000 unit (43–50 mL) ampoules
ERRNVPHGLFRVRUJ
INDICATIONS
• History, clinical features and laboratory evidence of envenoming
(see Chapter 5.5: Taipan)
• Taipan envenoming characterised by neurotoxicity, venom-
induced consumptive coagulopathy (VICC) and myotoxicity
CONTRAINDICATIONS
ADMINISTRATION
20 minutes.
• Note: Antivenom can be given as a rapid IV push if the patient is
haemodynamically unstable or in cardiac arrest.

ANTIVENOMS

• Note: Taipan Antivenom halts the progression of paralysis.
Established neurotoxicity is not reversed by antivenom.

514
51

4

TOXICOLOGY HANDBOOK

description).
Serum sickness
ERRNVPHGLFRVRUJ
HANDY TIPS
• Taipan Antivenom does not reverse established paralysis. Instead,
it halts the progression of paralysis.
• One ampoule of Polyvalent Antivenom may substitute for one
ampoule of Taipan Antivenom.
PITFALLS
reactions.
envenomed.
CONTROVERSIES
ANTIVENOMS
defined.
• Some authors recommend further doses of antivenom for severe
envenoming; however, current evidence suggests that a single
ampoule of either Taipan or Polyvalent Antivenom is sufficient to
neutralise all circulating antivenom in the severely envenomed
patient.
References 515
35(9):1532–1538.
Isbister GK, Buckley NA, Page CB et al. A randomized controlled trial of fresh frozen TOXICOLOGY HANDBOOK
plasma for treating venom-induced consumption coagulopathy in cases of
Australian snakebite (ASP-18). Journal of Thrombosis and Haemostasis 2013;
11:1310–1318.
102:563–568.
6.6 CSL SEA SNAKE ANTIVENOM

This equine IgG Fab is the specific treatment of envenoming by all
species of sea snake (family Hydrophiidae) found in Australian waters.
PRESENTATION
1000 unit (15–35 mL) ampoules
ERRNVPHGLFRVRUJ
INDICATIONS
• Clinical evidence of systemic envenoming with development of
neurotoxicity (paralysis and respiratory failure) (see Chapter 5.6:
Sea snake)
• Laboratory evidence of myotoxicity within 6 hours of the bite
CONTRAINDICATIONS
ADMINISTRATION
reaction.
• Administer 1 ampoule diluted in 500 mL of normal saline IV
over 20 minutes. Note: In the presence of progressive
neurological deterioration, 3 ampoules of antivenom should be
administered.
• A single dose is sufficient to halt progression of paralysis in most
ANTIVENOMS
cases. Following the initial dose, the patient is observed clinically

and spirometry/peak flow measurements monitored.
unstable or in cardiac arrest.

• Resolution or stabilisation of systemic features of envenoming
516
51

6

TOXICOLOGY HANDBOOK

description).
administration.
Serum sickness
ERRNVPHGLFRVRUJ
PITFALLS
envenomed.
CONTROVERSY
• Historically, other antivenoms (Tiger or Polyvalent) have been
recommended as alternatives where Sea Snake antivenom is
unavailable. Current data do not support this recommendation.
Reference
6.7 CSL POLYVALENT SNAKE ANTIVENOM
ANTIVENOMS
This equine IgG Fab is used in the treatment of envenoming by snakes in
Australia and Papua New Guinea. It contains antibodies to the eastern
brown snake (Pseudonaja textilis), mulga snake (Pseudechis australis),
common tiger snake (Notechis scutatus), common death adder
(Acanthophis antarcticus) and the coastal taipan (Oxyuranus scutellatus).
PRESENTATIONS 517
40 000 unit (~50 mL) ampoules containing:
1000 units Brown Snake Antivenom
3000 units Tiger Snake Antivenom
6000 units Death Adder Antivenom TOXICOLOGY HANDBOOK
12 000 units Taipan Antivenom
18 000 units Black Snake Antivenom
INDICATIONS
• Clinical or laboratory evidence of snake envenoming in Australia
or Papua New Guinea when the correct monovalent antivenom
cannot be identified or is not available
• Note: Polyvalent Antivenom is not required in Tasmania (Tiger
Snake Antivenom is recommended) or in Victoria and south-west
Western Australia (a combination of Brown Snake Antivenom and
Tiger Snake Antivenom is recommended).
CONTRAINDICATIONS
• Not indicated for the treatment of sea snake envenoming
ERRNVPHGLFRVRUJ
ADMINISTRATION
20 minutes.
• Note: Antivenom can be given as a rapid IV push if the patient is
haemodynamically unstable or in cardiac arrest.


description).
ANTIVENOMS

Serum sickness
518 • Oral steroids (e.g. prednisolone 50 mg/day or 1–2 mg/kg/day in
51

8

TOXICOLOGY HANDBOOK
HANDY TIP
• A patient envenomed by an unknown snake may usually be
appropriately treated with 1 or 2 (rarely, 3) monovalent
antivenoms dependent on geography, clinical features and
laboratory investigations. This is less expensive and carries a
lower risk of adverse reaction than use of Polyvalent Antivenom.
PITFALLS
envenomed.
ERRNVPHGLFRVRUJ
References
6.8 CSL STONEFISH ANTIVENOM

This equine IgG Fab is the specific treatment of envenoming by stonefish
(Synanceia trachynis and Synanceia verrucosa) from Australian waters. It
may also have a role in the treatment of bullrout (Notesthes robusta),
lionfish (Pterois volitans) and cobbler (Gymnapistes marmoratus) stings.
PRESENTATION
2000 unit (1.5–3 mL) ampoules
INDICATIONS
• Severe localised pain unrelieved by intravenous opioids
• Clinical evidence of systemic envenoming, such as cardiac failure
ANTIVENOMS
CONTRAINDICATIONS
ADMINISTRATION
519
• Administer 1 ampoule for every two spine puncture wounds (to a
maximum of 3 ampoules) undiluted by IM injection.
• Alternatively, the antivenom may be diluted in 100 mL normal TOXICOLOGY HANDBOOK
saline and administered intravenously over 20 minutes.
• Repeat doses of 1 ampoule are given until therapeutic end point
is achieved (see below).
haemodynamically unstable, or in cardiac arrest.

• Resolution of local and systemic features of envenoming

description).
ERRNVPHGLFRVRUJ
administration.
Serum sickness
Pregnancy: pregnancy is not a contraindication to either opioid analgesia or
antivenom.
Paediatric: give standard adult dose (in 10 mL/kg of normal saline if IV).
PITFALLS
• Failure to give repeat doses of antivenom following an absent,
incomplete or transient response to the initial dose.
ANTIVENOMS

reactions.
envenomed.
CONTROVERSY
520 • Relative efficacy of IM versus IV route of administration.
52
0
References
TOXICOLOGY HANDBOOK

41:301–308.
6.9 CSL BOX JELLYFISH ANTIVENOM

This ovine IgG Fab is available for treatment of envenoming by box
jellyfish (Chironex fleckeri) found in Australian waters. Its clinical utility is
questionable.
PRESENTATION
20 000 unit (1.5–4 mL) ampoule
INDICATIONS
• Clinical features of systemic envenoming, such as cardiovascular
instability and cardiac arrest (see Chapter 5.10: Box jellyfish)
• Local pain refractory to IV opioid analgesia
ERRNVPHGLFRVRUJ
CONTRAINDICATIONS
suspected ovine sera allergy
ADMINISTRATION
• In patients with pain refractory to IV opioid analgesia, administer 1
ampoule diluted in 100 mL of normal saline IV over 20 minutes.
Further doses of 1 ampoule may be given, to a total of 3
ampoules, if pain persists.
• Administer 3 ampoules diluted in 100 mL of normal saline IV over
20 minutes in patients with haemodynamic compromise. Repeat
doses of 3 ampoules are given until therapeutic end point is
achieved (see below).
• Note: Six ampoules may be given as a rapid IV push if the patient
is in cardiac arrest.
ANTIVENOMS
• Resolution of severe local pain

• Immediately cease antivenom infusion. 521
description).
TOXICOLOGY HANDBOOK
administration.
Serum sickness
ERRNVPHGLFRVRUJ
HANDY TIPS
• Most patients suffering local envenoming by box jellyfish do not
develop systemic features. Local pain usually settles with ice and
simple analgesia and antivenom is not required.
• CSL Box Jellyfish Antivenom is not effective in irukandji syndrome
or for stings by other jellyfish.
PITFALL
• Administration of antivenom to patients without clinical features of
systemic envenoming.
CONTROVERSIES
• Although antivenom is demonstrated to bind well to venom in
vitro, it does not appear to prevent venom-induced cardiovascular
collapse in vivo. This suggests that the venom acts very rapidly
on the cardiovascular system and before it can be bound by
antivenom. If correct, this means that antivenom is of limited
clinical value.
• Although commonly advocated in patients with severe pain, there
is only anecdotal evidence to support the use of antivenom for
analgesia.
• Antivenom is sometimes administered by the IM route, but this
ANTIVENOMS
route is almost certainly ineffective.
References
41:301–308.
Winter KL, Isbister GK, Jacoby T et al. An in vivo comparison of the efficacy of CSL box
522 jellyfish antivenom with antibodies raised against nematocyst-derived Chironex
fleckeri venom. Toxicology Letters 2009; 187:94–98.
52
2
6.10 CSL REDBACK SPIDER ANTIVENOM

TOXICOLOGY HANDBOOK
This equine IgG Fab is used in the treatment of envenoming by the

Australian redback spider (Latrodectus hasselti).
PRESENTATION
500 unit (1–1.5 mL) ampoules
INDICATIONS
• Local pain refractory to simple analgesia
• Clinical features of systemic envenoming (latrodectism) (see
Chapter 5.13: Redback spider)
• Therapeutic trial may be warranted when diagnosis uncertain
CONTRAINDICATIONS
• Increased risk of allergic reaction in patients who have been
ERRNVPHGLFRVRUJ
ADMINISTRATION
reaction.
• Administer 2 ampoules diluted in 100 mL of normal saline IV
over 20 minutes.

• Acute hypersensitivity reactions occur in less than 5% of cases
following IV administration of diluted antivenom and generally are
of mild severity (e.g. skin rash).
• Give oxygen, IV fluids and consider administration of IM
adrenaline 0.01 mg/kg (max 0.5 mg) to lateral thigh (see
Appendix 6 for full management description).
ANTIVENOMS
administration.
Serum sickness
• This relatively benign and self-limiting complication occurs 5–10
days after antivenom in about 10% of cases.
• Oral steroids (e.g. prednisolone 50 mg/day in adults or 523
1–2 mg/kg/day in children for 5 days) ameliorate symptoms.
TOXICOLOGY HANDBOOK
Pregnancy: pregnancy is not a contraindication for antivenom treatment.
Antivenom administration may have successfully reversed premature labour
caused by redback spider envenoming.
Lactation: no restrictions on use.
HANDY TIP
• Redback antivenom may be used as a diagnostic (and
therapeutic) tool in patients who present with clinical features of
envenoming, but no history of bite.
PITFALLS
woman due to concerns about the potential adverse reactions.
Children receive the same dose of antivenom as adults, but
dilution may need to be adjusted to a suitable volume.
ERRNVPHGLFRVRUJ
CONTROVERSY
• The clinical value of antivenom administration in the management
of latrodectism has recently been questioned with a randomised
controlled study in adults (RAVE II) suggesting that it does not
provide significant clinical benefit above that of standard
analgesia in control of the pain and systemic symptoms of
redback envenoming.
References
Isbister GK. Safety of i.v. administration of redback spider antivenom. Internal Medicine
Journal 2007; 37:820–822.
Isbister GK, Brown SGA, Miller M et al. A randomised controlled trial of intramuscular
versus intravenous antivenom for latrodectism – the RAVE study. Quarterly Journal
of Medicine 2008; 101:557–565.
Isbister GK, O’Leary MA, Miller M et al. A comparison of serum antivenom
concentrations after intravenous and intramuscular administration of redback
(widow) spider antivenom. British Journal of Clinical Pharmacology 2008;
65:138–143.
Isbister GK, Page CB, Buckley NA et al. Randomised controlled trial of intravenous
antivenom versus placebo for lactrodectism: the second redback antivenom
evaluation (RAVE II) study. Annals of Emergency Medicine 2014; 64:1–9 (In press).
ANTIVENOMS
6.11 CSL FUNNEL-WEB SPIDER ANTIVENOM

This lapine IgG Fab is the definitive treatment of envenoming by funnel-
web spiders (Atrax spp. and Hadronyche spp.). It may also be useful in
treating envenoming by mouse spiders (Missulena bradleyi).
524
52
PRESENTATION
4
125 units per ampoule of freeze-dried antivenom

TOXICOLOGY HANDBOOK
INDICATIONS
• Clinical features of systemic envenoming
• Usually these features are dramatic and sudden in onset and
commence with perioral tingling, tongue fasciculation, salivation,
sweating and lacrimation. They may progress to muscle
twitching, tachycardia and hypertension, pulmonary oedema
and death.
CONTRAINDICATIONS
• No specific contraindications
suspected lapine sera allergy
ADMINISTRATION
• Reconstitute the freeze-dried antivenom in 10 mL of sterile water.
ERRNVPHGLFRVRUJ
• Administer 2 ampoules diluted in 100 mL of normal saline IV over
20 minutes. Note: In the severely envenomed patient, the
recommended initial dose is 4 ampoules.
• Repeat doses of 2 ampoules are given every 2 hours until clinical
features of envenoming resolve.


description).
Serum sickness
ANTIVENOMS
Pregnancy: no restriction on use. 525
TOXICOLOGY HANDBOOK
PITFALLS
• Failure to give repeat doses of antivenom following an absent,
incomplete or transient response to the initial dose.
• Inadequate initial dose with life-threatening envenoming.
woman due to concerns about the potential adverse reactions.
envenomed.
Reference
ERRNVPHGLFRVRUJ
APPENDIX 1: POISONS INFORMATION TELEPHONE
NUMBERS
Australia 13 11 26
New Zealand 0800 764 766/0800 POISON
United Kingdom 0870 6006266
United States of America 1 800 2221222

APPENDICES
528
52
8
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
APPENDIX 2: EXAMPLE ECGs
Appendix 2A TCA Cardiotoxicity
APPENDICES
529
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
Appendix 2B TCA Cardiotoxicity (Post-alkalinisation)
APPENDICES
530
53
0
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
Appendix 2C Acute Digoxin Overdose
APPENDICES
531
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
Appendix 2D QT Prolongation and Torsades De Pointes
APPENDICES
532
53
2
TOXICOLOGY HANDBOOK
ERRNVPHGLFRVRUJ
•
•
Conventional SI
Therapeutic Conversion Therapeutic

Drug range Units factor range Units
Carbamazepine 4–12 mg/L 4.25 17–51 micromol/L
Digoxin 0.8–2.0 ng/mL 1.281 1.1–2.6 nmol/L

conversion factor
conversion factor
Ethanol N/A mg/dL 0.217 N/A mmol/L
Ethylene glycol N/A mg/L 16.11 N/A micromol/L
Iron 80–180 microgram/dL 0.179 14–32 micromol/L
Lead <10 microgram/dL 0.0483 <0.48 micromol/L
Paracetamol 10–30 microgram/mL 6.62 66–199 micromol/L

IMPORTANT TOXINS
ERRNVPHGLFRVRUJ
Phenobarbitone 15–40 mg/L 4.31 65–172 micromol/L
Phenytoin 10–20 microgram/mL 3.96 40–79 micromol/L

THERAPEUTIC RANGES FOR
APPENDIX 3: CONVERSION FACTORS AND
Salicylate 15–30 mg/dL 0.0724 1.1–2.2 mmol/L

To convert from SI units to conventional units, divide by
Theophylline 5–15 microgram/mL 5.55 28–83 micromol/L

To convert from conventional units to SI units, multiply by
Valproic acid 50–120 mg/L 6.94 347–833 micromol/L
TOXICOLOGY HANDBOOK APPENDICES

533
APPENDIX 4: ALCOHOL PATHWAYS
Pathways of Alcohol Metabolism
Ethanol Ethylene Glycol
Ethanol Ethylene glycol

ADH NAD ADH NAD
NADH NADH
Acetaldehyde Glycoaldehyde
ALDH ALDH
Acetate Glycolic acid

Mg++
Thiamine Pyridoxine
APPENDICES
Acetyl CoA Alpha hydroxy- Glyoxylic acid Glycine

beta-ketoadipate
Thiamine Thiamine
CO2 + H2O Oxalic acid
534 Methanol Isopropanol

53
4
Methanol Isopropyl alcohol

TOXICOLOGY HANDBOOK
ADH NAD
NADH ADH
Formaldehyde Acetone
ALDH
Formic acid
ADH: Alcohol dehydrogenase
Folate
ALDH: Aldehyde dehydrogenase
CO2 + H2O
ERRNVPHGLFRVRUJ
APPENDIX 5: THERAPEUTIC OVER-WARFARINISATION
Guidelines for the management of adult patients on warfarin therapy
with bleeding or with an elevated international normalised ratio (INR)
without bleeding
5A MANAGEMENT OF ADULT PATIENTS ON WARFARIN THERAPY WITH

BLEEDING*
Clinical setting Recommendations and levels of evidence†
INR ≥ 1.5 with Cease warfarin therapy and administer:

life-threatening‡ (critical ● vitamin K1 5.0–10.0 mg IV (2C)
organ) bleeding ● and Prothrombinex-VF 50.0 IU/kg§ IV (GPP)
● and fresh frozen plasma 150–300 mL (GPP)
● If Prothrombinex-VF is unavailable, administer
fresh frozen plasma 15 mL/kg (GPP)
INR ≥ 2.0 with clinically Cease warfarin therapy and administer:
APPENDICES
significant bleeding ● vitamin K1 5.00–10.0 mg IV (2C)
(not life-threatening) ● and Prothrombinex-VF 35.0–50.0 IU/kg IV
(GPP) according to INR (see 5B)
● If Prothrombinex-VF is unavailable, administer
fresh frozen plasma 15 mL/kg (GPP)
Any INR with minor ● Omit warfarin, repeat INR the following day
bleeding and adjust warfarin dose to maintain INR in 535
the target therapeutic range (2C)
● If bleeding risk is high** or INR > 4.5, consider
vitamin K1, 1.0–2.0 mg orally or 0.5–1.0 mg IV
TOXICOLOGY HANDBOOK
(GPP)
INR = international normalised ratio; IV = intravenously.
Note: vitamin K1 = phytomenadione.
*Indication for warfarin therapy should be reviewed; if clinically appropriate, consider
permanent cessation.
†
Level of evidence in parentheses in bold; details, see 5C.
‡
Includes intracranial bleeding.
§
Consider administering a Prothrombinex-VF dose < 50.0 IU/kg when INR 1.5–1.9.
**Recent major bleed (within previous 4 weeks) or major surgery (within previous 2
weeks), thrombocytopenia (platelet count, < 50 × 109/L), known liver disease or
concurrent antiplatelet therapy.
Reproduced from Tran HA, Chunilal SD, Harper PL et al. An update of consensus
guidelines for warfarin reversal. Medical Journal of Australia 2013; 198(4):198–199.
ERRNVPHGLFRVRUJ
5B MANAGEMENT OF ADULT PATIENTS ON WARFARIN THERAPY WITH HIGH INR
AND NO BLEEDING
Clinical setting Recommendations and levels of evidence*
INR higher than the Lower or omit the next dose of warfarin
therapeutic range but Resume therapy at a lower warfarin dose when the
< 4.5 and no bleeding INR approaches therapeutic range
• If the INR is only minimally above therapeutic
range (up to 10%) dose reduction is generally
not necessary (2C)
INR 4.5–10.0 and no • Cease warfarin therapy; consider reasons for

bleeding elevated INR and patient-specific factors.
Vitamin K1 is usually unnecessary (2C)
• If bleeding risk is high:†
• consider vitamin K1 1.0–2.0 mg orally or
0.5–1.0 mg IV (GPP)
• measure INR within 24 h
• resume warfarin at a reduced dose once INR
APPENDICES
approaches therapeutic range
INR > 10.0 and no • Cease warfarin therapy, administer 3.0–5.0 mg

bleeding vitamin K1 orally or IV‡ (2C)
• Measure INR in 12–24 h. Close monitoring of
INR daily to second daily over the following
week (GPP)
536 • Resume warfarin therapy at a reduced dose
53
once INR approaches therapeutic range

6
• If bleeding risk is high: †

TOXICOLOGY HANDBOOK
• consider Prothrombinex-VF, 15–30 IU/kg (GPP)

• measure INR in 12–24 h. Close monitoring over
the following week
• resume warfarin therapy at a reduced dose
once INR approaches therapeutic range
INR = international normalised ratio; IV = intravenously.
Note: vitamin K1 = phytomenadione.
*Level of evidence in parentheses in bold; details, see 5C. Recommendations with no
evidence are standard practice and not based on gradable evidence.
†
Recent major bleed (within previous 4 weeks) or major surgery (within previous 2
weeks), thrombocytopenia (platelet count, < 50 × 109/L), known liver disease or
concurrent antiplatelet therapy.
‡
Extrapolated from oral vitamin K data in absence of IV data.
ERRNVPHGLFRVRUJ
5C GRADES OF GUIDELINE RECOMMENDATIONS
Grade of recommendation Quality of supporting evidence
Strong recommendation, Evidence obtained from a systematic

high-quality evidence (1A) review of all relevant randomised
controlled trials (RCTs) or exceptionally
strong evidence from observational
studies
Strong recommendation, Evidence from at least one RCT or very

moderate-quality evidence (1B) strong evidence from observational
studies
Strong recommendation, Evidence for at least one critical outcome

low-quality evidence (1C) from observational studies, case series,
or RCTs, with serious flaws or indirect
evidence
Weak recommendation, Evidence obtained from a systematic
APPENDICES
high-quality evidence (2A) review of all relevant RCTs or
exceptionally strong evidence from
observational studies
Weak recommendation, Evidence from at least one RCT or very

moderate-quality evidence (2B) strong evidence from observational
studies
537
Weak recommendation, low- or Evidence for at least one critical outcome
very low-quality evidence (2C) from observational studies, case series,
or RCTs, with serious flaws or indirect
TOXICOLOGY HANDBOOK
evidence
Good practice point (GPP) Supporting evidence is insufficient to

meet even the lowest grade of evidence.
Recommendation is therefore based on
consensus opinion of the writing panel of
Australasian Society of Thrombosis and
Haemostasis
ERRNVPHGLFRVRUJ
APPENDIX 6: MANAGEMENT OF ALLERGIC
REACTIONS TO ANTIVENOMS
1 MANAGEMENT OF ACUTE SEVERE ALLERGIC REACTION OR ANAPHYLAXIS
Initial management
• Call for assistance.
• Administer adrenaline IM (lateral thigh) 0.01 mg/kg up to 0.5 mg.
• Lay flat/elevate legs if tolerated.
• Administer high-flow oxygen, airway/ventilation support if needed.
• Intravenous normal saline bolus 20 mL/kg if hypotensive.
Inadequate response or further deterioration
• Commence IV adrenaline infusion (1 mg of adrenaline in 100 mL
normal saline and commence at 0.5–1 mL/kg/hour then titrate to
response)
or
• Repeat IM adrenaline 0.01 mg/kg up to 0.5 mg every 3–5 minutes
as needed.
APPENDICES
• If persistent hypotension, repeat normal saline boluses

10–20 mL/kg up to 50 mL/kg over 30 minutes.
• If severe bradycardia, administer atropine IV 0.02 mg/kg.
• If bronchospasm, administer continuous salbutamol nebules and
hydrocortisone IV 5 mg/kg.
• If upper airway obstruction, administer adrenaline nebulised 5 mg
538 in 5 mL.
53
Infusion of antivenom is recommenced cautiously as soon as clinical

8
manifestations of anaphylaxis are controlled. Rarely, ongoing

TOXICOLOGY HANDBOOK
administration of adrenaline by titrated infusion may be necessary to

complete antivenom administration.
2 MANAGEMENT OF SERUM SICKNESS

This is a benign and self-limiting condition, but responds well to a
short course of oral steroids (e.g. oral prednisolone 50 mg daily for
5 days).
Adapted from Brown SG, Mullins RJ, Gold MS. Anaphylaxis diagnosis and
management. Medical Journal of Australia 2006; 185(5):283–289.
ERRNVPHGLFRVRUJ

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TOXICOLOGY

National Library of Australia Cataloguing-in-Publication entry

Professor Frank FS Daly MBBS FACEM LWA

Two of the original authors of the Toxicology Handbook were not

Lindsay Murray Alan Gault

Ioana Vlad MD FACEM, Consultant Emergency Physician and Clinical

Acute poisoning is a common emergency medicine presentation.

likely clinical course and potential complications for the individual at

that particular presentation. Risk assessment should wherever possible be

will also be of use to ambulance and emergency paramedic personnel

suffering from exacerbation of very significant underlying psychiatric,

diagnosis in a patient with cardiac arrest, resuscitation (see Table 1.2.1)

should continue until expert advice can be obtained. Extracorporeal

AIRWAY, BREATHING AND CIRCULATION

TABLE 1.2.1 Resuscitation

APPROACH TO THE POISONED PATIENT

DETECT AND CORRECT SEIZURES

DETECT AND CORRECT HYPOGLYCAEMIA

Life-threat Mechanism Agent(s) Comments

Airway Corrosive injury to ● Alkalis ● Stridor, dysphagia and dysphonia indicate

Hypoventilation Opioid mu receptor ● Opioids ● Prompt administration of naloxone may

Respiratory failure Cholinergic crisis ● Carbamates ● Rapid administration of atropine by serial

Hypoxaemia Oxygen free radical- ● Paraquat ● Avoid supplemental oxygen; if hypoxia

Ventricular Hypocalcaemia ● Hydrofluoric acid ● Defibrillation alone unlikely to be efficacious

Ventricular Fast Na+ channel ● Chloroquine/ ● Cardioversion or defibrillation unlikely to be